3. Monogenic Causes of ADHD

“Monogenic causes” refers to genes in which certain genetic variants can trigger disorders associated with ADHD symptoms.
In rare cases, a single genetic defect can lead to ADHD.¹
In addition, we have included chromosomal aberrations here, even though they affect all genes on the chromosome and are therefore not a monogenic cause. However, they are a monocausal genetic cause, which is why we mention them in this context.

Since a gene can have various mutations that (in the case of protein-coding genes) can result in a wide range of changes in protein activity (no protein activity at all, slightly reduced, normal, slightly increased, greatly increased…), monogenic disorders can also manifest in different severities or forms. Therefore, not every gene mutation in one of the genes listed here leads to ADHD. We have included genes as monogenic causes of ADHD when certain variants are associated with a significantly increased prevalence of ADHD. The numbers in parentheses indicate the ADHD prevalence for specific gene variants of the named gene. These figures should be interpreted with caution, particularly when the number of affected individuals is very small.

In addition to the genes listed here, there are numerous animal models in which a single gene has been inactivated, causing them to develop ADHD symptoms (up to and including the full-blown form of the disorder). These genes also represent monogenic causes of ADHD.
Many monogenic disorders are rare (orphan) diseases. Currently, about 8,000 rare diseases are known. Of these, ICD-10 lists only about 500 with their own codes. ICD-11 will go much further in this regard.²

The candidate genes listed below very rarely occur as dysfunctional gene variants. According to current understanding, ADHD is generally not a monogenic disorder. We, however, consider it entirely possible that monogenic causes could account for a significant proportion of ADHD cases.

The percentages in the headings indicate the prevalence of ADHD among people with the respective dysfunctional gene variant.

1. Monogenic Causes of ADHD¶

1.1. FMR1, Fragile X syndrome, FXS (full mutation: 42 to 59%; premutation: 93%)¶

The prevalence of Fragile X syndrome is:

• Full mutation
  • 1 in 3,600 to 1 in 4,000 for men and approximately 1 in 4,000 to 1 in 6,000 for women³
  • 1 in 7,140 men and 1 in 11,000 women⁴
• Premutation
  • 1 in 855 for men and 1 in 291 for women⁴

Fragile X syndrome is the most common genetic cause of intellectual disability after trisomy 21 (Down syndrome).³

Fragile X syndrome (FXS) is caused by a full mutation expansion (more than 200 CGG repeats) in the FMR1 gene, which leads to a deficiency of the Fragile X mental retardation protein (FRMP).⁵ Although most individuals with the premutation (55 to 200 CGG repeats) are considered unaffected by FXS, recent case studies have documented children with the premutation who exhibit cognitive deficits, behavioral problems, and/or autism spectrum disorders. ⁵
The Absence of FMRP

• impairs DAGL transport and the formation of functional postsynaptic mGluR5-DAGL complexes.⁶ This results in ectopic production of the endocannabinoid 2-AG, which in turn overstimulates presynaptic CB1R receptors, leading to their desensitization and internalization. The absence of FMRP impairs the on-demand release of 2-AG via DAGL. Consequently, the effects of 2-AG on feedback inhibition and synaptic plasticity are absent. Consequently, the 2-AG-mediated regulation of glutamate and GABA signaling is impaired. The lack of synaptic plasticity impairs learning, memory, and the regulation of behavior and emotion.⁷
• impairs homeostatic neural plasticity by blocking synaptic retinoic acid signaling⁸
  • Retinoic acid receptors influence dopamine levels; see Retinoic acid receptors influence the dopamine system In the article How Dopamine Is Regulated in the subsection Dopamine in the section Neurotransmitters in ADHD in the chapter Neurological Aspects

Fragile X syndrome is considered a monogenic cause of ASD.
The prevalence of ADHD and intellectual disability is also higher.⁹
ADHD Prevalence:

• 54 to 59% in a study of 63 boys with the full mutation¹⁰
• 42% in a study of 31 boys¹¹
• 93% of 43 boys with the premutation exhibited ADHD symptoms. 79% exhibited ASD symptoms. Carriers of the premutation exhibited developmental problems, particularly those who had clinical behavioral abnormalities.⁵

A study found no correlation between the FMR1 premutation and ADHD or anxiety in women (8% increased risk)¹², although it only determined the diagnostic prevalence, which can be misleading for underdiagnosed conditions such as ADHD.¹³

1.2. THRB, thyroid hormone β-receptor gene (40% to 88%)¶

A genetically determined dysregulation of the TH-beta receptor can cause elevated blood thyroxine levels due to resistance to thyroid hormone β.
The prevalence of THRB resistance is estimated to be between 1 in 19,000 and 1 in 40,000.¹⁴

People with ADHD have a high prevalence of ADHD symptoms:

• Hyperactivity
  • 88% (n = 65)¹⁵
  • 35% to 72%¹⁶
• Emotional dysregulation
  • 88% (n = 65)¹⁵
  • 73%¹⁶
• ADHD symptoms
  • 70%¹⁷
  • 70% of children¹⁸
  • 50%¹⁹
  • 40 to 46%¹⁶

The findings revealed evidence of increased connectivity between regions of the default-mode network and the dlPFC, as well as weaker connectivity between the lingual gyrus and the bilateral insula (salience network). The former is associated with ADHD involving attention problems, while the latter is associated with ADHD characterized by reduced habituation to visual stimuli and increased distractibility.

Both hypothyroidism and hyperthyroidism cause cognitive changes. Depending on the severity of the hypothyroidism, the cognitive effects can range from mild impairments in memory and attention to full-blown dementia. Hyperthyroidism can cause inattention and hyperarousal, among other cognitive deficits.²⁰²¹

The THRB gene encodes the thyroid receptor isoforms TRβ1 and TRβ2, while the THRA gene encodes the thyroid receptor alpha, TRα1.
The pituitary hormone TSH (thyroid-stimulating hormone) stimulates the thyroid gland to produce thyroxine (T4; prohormone) and subsequently triiodothyronine (T3). The thyroid hormones (T3 and T4) in the blood, in turn, regulate the pituitary release of TSH within the hypothalamic-pituitary-thyroid axis, which is mediated by the receptor isoform TRβ2.
In cases of resistance to thyroid hormone β, this negative feedback loop—which stabilizes TH levels in the blood—is disrupted. This leads to elevated TH levels and unsuppressed, i.e., normal, TSH levels.¹⁹

1.3. CAPRIN1, Cell Cycle-Associated Protein 1 (82%)¶

Prevalence: So far, only 15 people with CAPRIN1 haploinsufficiency appear to have been identified.

Other names: Caprin-1; RNG105; GPI-Anchored Membrane Protein 1; GPIAP1; M11S1; Cytoplasmic Activation- and Proliferation-Associated Protein 1; Cytoplasmic Activation/Proliferation-Associated Protein-1; Membrane Component, Chromosome 11, Surface Marker 1; GPI-Anchored Protein P137; RNA Granule Protein 105; GPI-P137; GPIP137; P137GPI; Membrane Component, Chromosome 11, Surface Marker 1; Activation/Proliferation-Associated Protein 1; Cell Cycle-Associated Protein 1; Caprin 1; GRIP137

The CAPRIN1 protein mediates RNA-binding activity. CAPRIN1 may be involved in the negative regulation of translation and the positive regulation of dendritic spine morphogenesis. CAPRIN1 is located at the cell leading edge and in the cytosol.
CAPRIN1 is associated with

• Moyamoya angiopathy

Related paths:

• RNA binding
• RNA binding

Paralog: CAPRIN2

CAPRIN1 can regulate the transport and translation of mRNAs encoding proteins involved in synaptic plasticity in neurons and in cell proliferation and migration in various cell types. CAPRIN1 binds directly and selectively to MYC and CCND2 mRNAs. In neuronal cells, CAPRIN1 directly binds to several mRNAs associated with RNA granules, including BDNF, CAMK2A, CREB1, MAP2, and NTRK2 mRNAs, as well as GRIN1 and KPNB1 mRNAs, but not to rRNAs.²²

Haploinsufficiency of the CAPRIN1 gene is an autosomal dominant Disorder associated with loss-of-function variants in cell cycle-associated protein 1 (CAPRIN1).
The CAPRIN1 protein regulates the transport and translation of neuronal mRNAs that are critical for synaptic plasticity, as well as mRNAs that encode proteins important for cell proliferation and migration in various cell types.
Loss-of-function CAPRIN1 variants were associated with the following symptoms:²³

• Speech impairment/speech delay (100%)
• intellectual disability (83%)
• ADHD (82%)
• ASS (67%)
• Breathing problems (50%)
• Abnormalities of the limbs and skeleton (50%)
• Developmental delays (42%)
• Feeding problems (33%)
• Seizures (33%)
• Eye problems (33%)

1.4. PHF21A, PHD Finger Protein 21A (78% to 80%)¶

The prevalence of PHF21A dysfunction is unknown. Only about 20 cases have been reported to date. Unverified reports suggest an incidence of 1 in 1,100,000.

Other names: BHC80; KIAA1696; BM-006; BRAF35-HDAC Complex Protein BHC80; BHC80a; BRAF35/HDAC2 Complex (80 kDa); IDDBCS; NEDMS

The PHF21A gene encodes the BHC80 protein, which is a component of the BHC complex. The BHC complex mediates the repression of neuron-specific genes in non-neuronal cells via the cis-regulatory element (repressor element-1, RE1; neural restrictive silencer, NRS, NRSE). The BHC complex is recruited by REST to RE1/NRSE sites and acts as a chromatin modifier by deacetylating and demethylating specific sites on histones. Within the BHC complex, BHC80 may function as a scaffold. BHC80 inhibits KDM1A-mediated demethylation of ‘Lys-4’ on histone H3 in vitro, suggesting a role in the regulation of demethylation.²⁴

PHF21A is associated with:²⁵

• Intellectual developmental disorder with behavioral abnormalities
  • severe (37.5%
  • moderate (25%)
  • mild (37.5%)
• craniofacial dysmorphism with or without seizures
• Potocki-Shaffer syndrome
• epileptic phenotype (58.33%)
• Developmental and Epileptic Encephalopathy (DEE) (71.42%)
  • Of the 5 patients with DEE, three developed infantile epileptic seizure syndrome (IESS)
  • The seizures in 2 patients (2 out of 5, 40%) were controlled with anticonvulsant medications
• Overgrowth (100% of 12 people with ADHD)
• Hypotension (70%)
• Sleep disorders (33.33%)
• ADHD
  • 80% of the 5 people with ADHD for whom information on ADHD was available²⁶
  • 77.78% of the 12 known people with ADHD²⁵
• ASS
  • 50% of the 12 people with ADHD²⁵
  • 50% of the 6 people with ADHD for whom information on ASA was available²⁶

Related metabolic pathways:

• Infectious diseases
• Chromatin organization

Paralog: PHF21B

1.5. CHD2, Chromodomain Helicase DNA-Binding Protein 2 (65%)¶

Other names: Chromodomain-Helicase-DNA-Binding Protein 2; ATP-Dependent Helicase CHD2; DKFZp686E01200 2; DKFZp547I1315; DKFZp781D1727; FLJ38614; CHD-2; EC 3.6.4.12; EC 3.6.1; DEE94; EEOC
The prevalence of CHD2 dysfunction is unknown. Only about 225 cases have been reported to date.

The CHD2 gene encodes an ATP-dependent enzyme involved in chromatin remodeling.
Pathogenic variants in CHD2 are very rare (orphan). There are 225 known diagnosed patients from 28 countries who carry various allelic variants in CHD2, including small intragenic deletions/insertions as well as missense, nonsense, and splice site variants.²⁷

65% (11 out of 17) of people with CDH2 gene mutations had ADHD, and 57% had ASD.²⁷

1.6. SETBP1 haploinsufficiency (65%)¶

The prevalence of SETBP1 haploinsufficiency is unknown. Only about 34 cases have been reported to date.²⁸

All individuals with SETBP1 haploinsufficiency syndrome (SETBP1-HD) or SETBP1-related disorders (SETBP1-RD) exhibited neurological impairments, including intellectual disability/developmental delay (IDD), attention-deficit/hyperactivity disorder, autism spectrum disorder, and/or seizures, as well as language and speech delays.²⁹
In SETBP1 haploinsufficiency syndrome, the following was found:

• ADHD in 65%
• 21% had ASD, of whom 75% also had ADHD as a comorbid condition

1.7. DYRK1A, dual-specificity tyrosine phosphorylation-regulated kinase 1A (62%)¶

The prevalence of DYRK1A dysfunction is very low and is estimated to be less than 1 in 1,100,000.

DYRK1A syndrome is a form of intellectual disability.
A study found evidence of ADHD in 18 of the 29 people with ADHD (62%).³⁰

Common symptoms of DYRK1A syndrome include:

• Intellectual disability
• Delayed speech development
• Motor problems
• Microcephaly (small head)
• Feeding problems
• Eye problems
• Behavioral problems
• Seizures
• Reduced height growth
• Symptoms of autism

1.8. TSC1, TSC Complex Subunit 1 (30 to 60%)¶

Other names: TSC Complex Subunit 1; Hamartin; KIAA0243; LAM; TSC; Tuberous Sclerosis 1 Protein; Tuberous Sclerosis 1, TSC-1
The prevalence of TSC1 dysfunction ranges from 1 in 30,000 to 1 in 6,000.

TSC1 is believed to be a tumor suppressor gene that encodes the growth-inhibiting protein hamartin. Hamartin interacts with and stabilizes the GTPase-activating protein tuberin. This hamartin-tuberin complex inhibits mTORC1 signaling (mammalian target of rapamycin complex 1), which is a key regulator of anabolic cell growth. Hamartin also acts as a co-chaperone for Hsp90, inhibiting its ATPase activity. Hamartin facilitates Hsp90-mediated folding of kinase and non-kinase clients, including TSC2, thereby preventing their ubiquitination and proteasomal degradation. TSC1 is involved in microtubule-mediated protein transport, but this appears to result from unregulated mTOR signaling. TSC1 acts as a co-chaperone for HSP90AA1 and facilitates HSP90AA1-mediated chaperoning of protein clients such as kinases, TSC2, and the glucocorticoid receptor NR3C1. It increases ATP binding to HSP90AA1 and inhibits the ATPase activity of HSP90AA1. TSC1 competes with the activating co-chaperone AHSA1 for binding to HSP90AA1, thereby establishing a reciprocal regulatory mechanism for the chaperoning of client proteins. TSC1 recruits TSC2 to HSP90AA1 and stabilizes TSC2 by preventing the interaction between TSC2 and the ubiquitin ligase HERC1.³¹

Tsc1-mTORC1 signaling regulates striatal dopamine release **** , and cognitive flexibility.³²

TSC1 is associated with

• tuberous sclerosis
• Lymphangioleiomyomatosis

Related signal paths:

• mTOR signaling
• Gene expression (transcription)

Tuberous sclerosis is associated with ADHD in 30 to 60% of people with ADHD³³³⁴ and with neuropsychiatric manifestations such as ADHD, ASD, or intellectual disability in 90% of cases.³⁵
The Austrian Tuberous Sclerosis Association offers the TAND Checklist for Tuberous Sclerosis .

TSC2-KO mice also exhibit tuberous sclerosis-associated neuropsychiatric disorders and epilepsy. Female TSC2-KO mice showed more severe manifestations of hyperactivity and cognitive disorders. TSC-associated disorders are thought to be caused by hyperactivation of the Mechanistic Target of Rapamycin Complex 1 (mTORC1). mTORC1 inhibitors improve nearly all TSC symptoms. The mTORC1 inhibitor sirolimus improved TSC-associated neuropsychiatric disorders in TSC2-KO mice by modulating steroid levels in the brain and regulating E2/ERα-dependent transcriptional activation. Sirolimus may potentially be useful for treating TSC-associated neuropsychiatric disorders as well as diseases caused by sex-specific differences and steroid levels.³⁶

1.9. ANK3, ANKYRIN 3 (57%)¶

Other names: Ankyrin 3; Ankyrin 3, Node of Ranvier (Ankyrin G); Ankyrin-G; Ankyrin-3; Ankyrin-3, Node of Ranvier; ANKYRIN-G; MRT37; ANK-3

The prevalence of ANK3 dysfunction is extremely low. One source cites 5 known cases worldwide³⁷, which, however, conflicts with the studies cited below³⁸, which report higher prevalence figures.

The scaffolding protein ankyrin-3 is immunologically distinct from the ankyrins ANK1 and ANK2. It is found at the axonal initial segment and at the nodes of Ranvier of neurons in the central and peripheral nervous systems. Within the nodes of Ranvier, where action potentials are actively transmitted, ANK3 serves as an intermediate binding partner for neurofascin and voltage-gated sodium channels. ANK3 is required for the normal clustering of voltage-gated sodium channels at the axon hillock and for the generation of action potentials.³⁹ ANK2 encodes a protein involved in calcium ion transport across the plasma membrane.⁴⁰
ANK3 is found in the human brain primarily in the cerebellum and, to a lesser extent, in the prefrontal cortex (PFC), hippocampus, corpus callosum, and hypothalamus. ANK3 plays a central role in regulating the localization of ion channels, membrane transporters, cell adhesion molecules, and cytoskeletal proteins. ⁴¹
There are associations between ANK3 and dopamine.⁴²⁴³ ANK3 is an essential component of AMPAR-mediated synaptic transmission and the maintenance of spiny morphology. ANK3 promotes the stability of somatodendritic GABA-ergic synapses in vitro and in vivo by counteracting the endocytosis of GABAA receptors.⁴⁴
ANK3 is expressed by oligodendrocytes, where it is found more on the glial side than on the axonal side of the nodes.⁴⁵ ANK3 regulates the β-catenin/Wnt signaling pathway, which plays a role in bipolar disorder.⁴⁶ A short ANK3 isoform is localized in dendritic spines and regulates NMDA receptor-dependent plasticity.⁴⁷ ANK3 accumulates in dendritic spines following chronic lithium treatment.⁴⁸ In bipolar disorder, ANK3 mRNA levels are elevated in the blood, although no increased expression was found in the brain.⁴⁹

ANK3 and Stress
Prenatal stress affects the interaction between the ANK3 protein and PSD95. ANK3 appears to influence the effects of early childhood stress on the development of psychiatric disorders.⁵⁰
Heterozygous ANK3+/- mice, as well as mice in which ANK3 was inactivated in the dentate gyrus, showed:⁵¹

• reduced anxiety
  • reversible with chronic lithium therapy
• increased motivation for rewards
  • reversible with chronic lithium therapy
    Ank3+/- mice showed increased sensitivity to chronic stress:
• increased susceptibility to depression-like behaviors
• elevated corticosterone levels

ANK3 is associated with

• PTSD⁵²
• Autism⁵³⁵⁴
• Brugada syndrome, a type of cardiac arrhythmia.
• bipolar disorder
  • including rs10994336, rs1938526, and rs9804190, among others⁴¹
• intellectual disability.

OMIM: ANK3, ANKYRIN 3

ANK3 is associated with ADHD.⁵⁵ A study identified this gene as one of the 51 most likely genetic candidates for ADHD.⁵⁶
ANK2 malformations were associated with a 5.55-fold increased risk of ADHD.⁴⁰ The study assumes an ADHD prevalence of 5% among children, which would imply an ADHD prevalence of 27.7% among those with an ANK2 malformation. This study also found that ANK2 was associated with a high rate of ADHD-ASD comorbidity.

Among 27 people with ADHD (16 with monoallelic and 11 with biallelic ANK3 variants), it was found that the phenotype is more severe in cases of biallelic variants. Phenotypically, the following were observed:³⁸

• Speech delay (92%)
• ASS (76%)
• intellectual disability (78%)
• Hypotension (65%)
• motor delay (68%)
• ADHD (57%)
• Sleep disorders (50%)
• Aggression/self-harm (37.5%)
• Epilepsy (35%)
• Ataxia (11%, all with biallelic variants)

Most monoallelic variants result in a truncated protein. The biallelic variants are almost exclusively missense mutations.
The mono- and biallelic variants appear to be localized differently in the three different ankyrin G isoforms, suggesting isoform-specific pathological mechanisms.

1.10. NF1, Neurofibromatosis Type 1 (28.9% to 53.8%)¶

Due to the large number of studies, the highest and lowest results were excluded when calculating the prevalence mentioned in the headline.

Other names: Von Recklinghausen disease, Recklinghausen’s disease, Recklinghausen neurofibromatosis, peripheral neurofibromatosis
Prevalence of approximately 1 in 3,500 (0.029%); one of the most common inherited neurological disorders. Neurofibromatosis type 1 is characterized by abnormalities of the skin and the central nervous system. Neurofibromatoses are nerve tumors.
Neurofibromatosis type 1 is a RASopathy.⁵⁷

The diagnostic criteria for neurofibromatosis type 1 are at least 2 of the following symptoms:⁵⁸

• Six or more café-au-lait spots (CAL) > 5 mm in diameter before puberty and > 15 mm after puberty.
• A freckle in the armpit or groin area.
• Two or more neurofibromas of any type, or a plexiform neurofibroma (PNF)
• Glioma of the optic tract
• Two or more iris nodules (detected by slit-lamp examination) or two or more choroidal anomalies (CAs, detected as irregular bright nodules by optical coherence tomography [OCT] or near-infrared imaging [NIR])
• Specific bone lesions such as cuneiform dysplasia, anterolateral bowing of the tibia, or pseudarthrosis of the long bones.
• A heterozygous pathogenic (= disease-causing) NF1 variant with an allele frequency of 50% in normal tissue, such as leukocytes.

ADHD is common in neurofibromatosis type 1:

• 79.3% of 29 children with NF1⁵⁷
  • ADHD-C 71.4%, ADHD-I 19.0%, ADHD-HI 9.5%
• 53.8%: In a survey, n = 109 parents of children with neurofibromatosis reported that 29.4% had severe ASD, 26.6% had moderate to mild ASD, and between 26% and 53.8% had ADHD.⁵⁹
• 49.4%: A study of 93 children with neurofibromatosis type 1 found ADHD in 46 of them.⁶⁰
• 45.4%: In a study of 531 people with neurofibromatosis type 1, data on ADHD were available for 207 participants. Among them, 45.4% had ADHD.⁶¹ This corresponds to a 9-fold increased risk of ADHD.⁶²
• 28.9%: Among 128 people with neurofibromatosis type 1 (53.1% girls), 28.9% (37/128) had ADHD, including 20 with ADHD-C, 15 with ADHD-I, and 2 with ADHD-HI. ADHD and ASD occur more frequently in individuals with neurofibromatosis type 1.⁶³⁶⁴
  Other comorbidities associated with neurofibromatosis type 1 included macrocephaly (head circumference more than 2 standard deviations above the age-adjusted mean, 37.5%), headaches (18.6%), cognitive impairments (7.8%), motor deficits (6.2%), and epilepsy (4.68%). MRI revealed T2-weighted hyperintensities in the basal ganglia and/or cerebellum (70.5%), optic nerve gliomas (25.8%), plexiform neurofibromas (9.3%), Type 1 Chiari malformation (6.7%), arachnoid cysts (5%), and central nervous system gliomas (3.1%).⁶⁵
• 10.5% at 36 months of age: A study found that 10.5% of children with NF1 already had ADHD at 36 months of age.⁶⁶
• A meta-analysis (k = 70, n = 3,653) found that, based on parental ratings, children with NF1 exhibited more severe symptoms of⁶⁷ compared to unaffected children
  • Inattention (Hedges’ g = 1.20)
  • Hyperactivity/Impulsivity (Hedges’ g = 0.85)
  • combined ADHD symptoms (Hedges’ g = 1.02)

Larger effect sizes for inattention and hyperactivity/impulsivity correlated with older age and lower intelligence quotient (IQ).⁶⁷

Children with NF1 and ADHD, and children with primary ADHD, exhibit similar deficits in attention and executive functions.
NF1 was associated with slower reaction times and more severe learning difficulties.⁶⁸

In 5 to 11% of people with NF-1, the condition is caused by a microdeletion syndrome associated with neurofibromatosis type 1.
Among 57 people with NF-1 microdeletion syndrome, the following were found:⁶⁹

• 28 people with ADHD, 4 with Type 2, 2 with Type 3, 9 with atypical deletions, and 14 with unspecified deletions
• 33 out of 41 (80.5%) had learning difficulties
• developmental delays in 39 out of 49 (79.6%)
• 35 out of 49 (71.4%) had expressive and/or receptive language delays
• 38 out of 56 (67.9%) describable facial features
• in 23 out of 42 (54.8%) cases of ADHD
• plexiform neurofibromas in 25 of 57 (43.8%)
• in 3 of 57 (5.2%) cases, malignant peripheral nerve sheath tumors
• Reduced IQ (between 50 and 96; 22 people with ADHD studied, 21 of whom were adults). Of the adults, the following had:
  • 14 out of 21 (66.7%) have a high school diploma
  • 4 out of 21 (19.0%) have some college experience.

In NF-1, a dopamine deficiency correlates with learning difficulties.⁷⁰ NF1 model mice showed reduced tyrosine hydroxylase expression in the striatum and VTA, as well as a 20% reduction in dopamine levels in the hippocampus and a 61% reduction in DARPP32 phosphorylation. Postsynaptic D1 receptor expression in the hippocampus was unchanged. A D1 agonist was able to reverse the resulting impairment of LTP.⁷⁰

The degradation of neurofibrin is regulated by the F-box protein FBXW11. A disorder of Fbxw11 due to a germline mutation or targeted genetic manipulation in the nucleus accumbens resulted in the following in male Nf1+/- mice (NF1 haploinsufficiency):⁷¹

• an increase in neurofibromin levels
• inhibition of Ras-dependent ERK phosphorylation
• addressing social learning deficits
• an improvement in impulsive behavior

1.11. Noonan syndrome spectrum disorders (51%)¶

Noonan syndrome spectrum disorders (NSSD) are RASopathies. The consequences of a monogenic disorder in various genes involved in the RAS/MAPK signaling pathway are NSSD. People with ADHD who have these disorders include, among others:⁵⁷

• PTPN11 (most common)
• SOS1
• RAF1
• RIT1
• KRAS
• NRAS
• BRAF

ADHD was found in people with a Noonan syndrome spectrum disorder (NSSD)

• at 51.1%⁵⁷
• 50% have current or early-onset ADHD⁷²
• at 36.1%⁷³

An ASS was found in 64.2% of cases.⁷³

1.12. CHD8-NDD (approx. 50%)¶

CHD8-related intellectual disability-autism-macrocephaly-tall stature syndrome is very rare, with an incidence of 1 in 1,100,000 cases,{{Orpha.net:

CHD8-associated neurodevelopmental disorder with overgrowth (CHD8-NDD) is characterized by:⁷⁴

• general overgrowth
  • Macrocephaly (usually in infancy) (in about 80%)
  • Growth spurt (usually during puberty) (in about 80%)
• Developmental delay/intellectual disability
  • most commonly, speech and motor delays
  • in cases of intellectual disability, usually only mild to moderate
• Autism spectrum disorder (in approximately 75 to 80 percent of cases)
  - ADHD (in about 50% of cases)
• neuropsychiatric problems
• neurological problems
• Sleep disturbances (in about 67%)
  • delayed onset of sleep
  • Frequent nighttime awakenings
• Gastrointestinal problems (in about 66%)
  • Constipation with or without episodes of diarrhea
• Hypotension (in about 30%)
• Anxiety (29%)
• Seizures (in about 10 to 15 percent of cases)
• Dystonia (rare)
• Chiari I malformation (rare)

1.13. SHANK2 (50%)¶

SHANK2 is very rare.

A deletion or a pathogenic sequence variant in the SHANK2 gene causes a SHANK2 disorder. This disorder is associated with ASD, intellectual disability, and developmental delays.
Among the 10 people with ADHD were:⁷⁵

• ASA at 90% (0.2% of all ASA cases⁷⁶ to 0.38% of all ASA cases)⁷⁷
• ADHD in 50% of cases
• mild to moderate developmental delays
• Sensory hyperreactivity and seeking behavior were more pronounced than sensory hyporeactivity
• Hypotension
• recurrent ear infections
• gastrointestinal abnormalities
• no similar dysmorphic facial features
• significantly higher adaptive functioning than in PMS

1.14. ANKRD11, Ankyrin Repeat Domain Containing 11, KBG syndrome (24% to 41%)¶

Other names: ANCO1; ANCO-1; LZ16; T13; Ankyrin Repeat Domain-Containing Protein 11; Ankyrin Repeats Containing Cofactor 1; Ankyrin Repeat-Containing Cofactor 1; Ankyrin Repeat Domain 11; Nasopharyngeal Carcinoma Susceptibility Protein
ANKRD11 dysfunction is very rare. Its prevalence is reported to be less than 1 in 1,000,000.

The ANKRD11 protein contains an ankyrin repeat domain. ANKRD11 inhibits ligand-dependent activation of transcription. ANKRD11 is a chromatin regulator that modulates histone acetylation and gene expression in neural progenitor cells. ANKRD11 can recruit histone deacetylases (HDACs) to the p160 coactivator/nuclear receptor complex to inhibit ligand-dependent transactivation. ANKRD11 plays a role in the proliferation and development of cortical neural progenitor cells. ANKRD11 may regulate bone homeostasis.⁷⁸
ANKRD11 is associated with:

• rare genetic intellectual disabilities
• KBG syndrome
  • KBG is a rare syndrome. Genetic variants in the ankyrin repeat domain 11 (ANKRD11) and deletions in 16q24.3 can cause KBG syndrome. In a group of 25 people with KBG, 24% had been diagnosed with ADHD.⁷⁹
    KBG goes hand in hand with⁸⁰
    • Macrodontia
    • Distinctive craniofacial features
    • Short stature
    • Skeletal abnormalities
    • global developmental delay
    • Seizures
    • intellectual disability
    • Hearing loss and/or middle ear infection
    • Vision problems
    • Cryptorchidism
    • Cardiopathy
    • Feeding problems

A survey of 91 people with ADHD revealed prevalence rates of⁸¹

• 48% anxiety disorders
• 44% autism
• 41% ADHD
• 37% hearing problems
• 37% high level of frustration
• 36% vision problems
• 31% seizures, of which
  • 52% were currently able to control it through medication or a ketogenic diet
  • had 30% treatment-resistant seizures
  • 22% have not had any seizures recently
  • None of the individuals currently experiencing seizures lived independently
• 31% misaligned teeth
• 29% gastrointestinal problems in adulthood
  • of which all are blockages
  • of which 73% are reflux cases
• 29% scoliosis
• 28% had difficulty falling asleep, and nearly half of them needed medications such as melatonin to fall asleep
• 27% lordosis or kyphosis
• 26% have trouble staying asleep
• 26% outbursts of anger
• 25% aggression toward oneself or others
• 23% gastrointestinal problems in childhood
• 22% enamel problems
• A 21% increase in sleep needs
• 19% problems with the palate
• 19% tooth decay
• 19% had too many teeth
• 19% depression
• 18% mood swings
• 18% sensory exploration behavior
• 15% hip problems
• 15% binge eating
• 12% Compulsions
• 12% tics
• 12% heart valve problems
• 11% decrease in appetite or anorexia
• 11% sensory avoidance behavior
• 9% sudden sleepiness during the day
• 9% high blood pressure
• 8% regression (loss of previously acquired skills)
• 8% keloid scars
• 8% arthritis
• 8% abnormal wound healing
• 5% osteoporosis
• 5% sleep apnea
• 4% restless legs syndrome.
• 4% sudden drop in activity
• 1% schizophrenia
• 1% borderline personality disorder

1.15. PAH, PKU, phenylketonuria (38% to 40%)¶

Other names: Følling’s disease, Fölling’s disease, phenylpyruvic acid oligophrenia, oligophrenia phenylpyruvica, hyperphenylalaninemia
Prevalence: 1 in 8,000 (0.0125%) to 1 in 16,000 (0.00625%)

Based on an ADHD prevalence of 8%, this would result in a +375% increase in the risk of ADHD.

Phenylketonuria (PKU) is a recessive disorder of phenylalanine metabolism caused by mutations in the phenylalanine hydroxylase gene. PKU leads to a significant excess of phenylalanine (hyperphenylalaninemia). Since phenylalanine and tyrosine cross the blood-brain barrier via the same transporters—and these transporters have a higher affinity for phenylalanine—an excess of phenylalanine in the blood results in insufficient tyrosine reaching the brain. Tyrosine is a precursor to dopamine, which is further converted into norepinephrine and epinephrine. Therefore, an excess of phenylalanine in the blood leads to a deficiency of dopamine, norepinephrine, and epinephrine in the brain.⁸²⁸³ In addition, an excess of phenylalanine causes changes in cerebral myelin and protein synthesis, as well as reduced levels of serotonin in the brain.⁸⁴ ADHD and phenylketonuria thus share a common feature: a dopamine deficiency.^{8586 87}

A meta-analysis found that 40% of people with PKU had ADHD and hyperactivity (meta-analysis, k = 8, n = 222).⁸⁸ A small study found an ADHD prevalence of 38% among people with phenylketonuria, despite adequate treatment.⁸⁹

People with phenylketonuria often exhibit symptoms of ADHD, with the subtypes involving hyperactivity appearing to be more common.^9091859293

In a pharmaceutical-funded study, treatment with sapropterin improved ADHD symptoms in patients with phenylketonuria.⁹⁴ A study suggests that BH4, which is helpful in treating PKU, may also be beneficial for ADHD.⁸⁷

A low-phenylalanine diet prevents most of the consequences of phenylketonuria, but only if it is started within the first few weeks of life.
The neuronal developmental disorder caused by PKU is mediated, among other things, by the dopamine deficiency resulting from PKU.⁹⁵ This is consistent with the dopaminergic developmental pathway of ADHD.⁹⁶ Furthermore, the fact that the low-phenylalanine diet can be discontinued in adulthood—that is, once brain development is complete—supports the notion that dopamine deficiency has a significant influence on brain development in PKU.

1.16. SRRM2, Serine/Arginine Repetitive Matrix 2 (36%?)¶

Other names: Serine/Arginine Repetitive Matrix 2; SRL300; KIAA0324; SRm300; Cwc21; Serine/Arginine-Rich Splicing Factor-Related Nuclear Matrix Protein of 300; KDa; Tax-Responsive Enhancer Element-Binding Protein 803; Ser/Arg-Related Nuclear Matrix Protein of 300 kDa; SR-Related Nuclear Matrix Protein of 300 kDa; Serine/Arginine Repetitive Matrix Protein; Splicing Coactivator Subunit SRm300; 300 kDa Nuclear Matrix Antigen; TaxREB803; Testicular Secretory Protein Li 53; RNA-Binding Protein; HSPC075; 300-KD; SRM300; CWF21
SRRM2 dysfunction is very rare. Among 1,000 people with developmental delays and intellectual disability, 2 were found to have this genetic disorder. Intellectual disability has a prevalence of 1.65%, and developmental delay has a prevalence of 6.5%.

SRRM2 is a protein-coding gene. It mediates C2H2 zinc finger domain-binding activity and protein N-terminus-binding activity. SRRM2 is found in the Cajal body and the nuclear spot. SRRM2 is involved in mRNA splicing as part of the U2-type catalytic step-2 spliceosome and the precatalytic U2 spliceosome. SRRM2 is a biomarker for Parkinson’s disease.⁹⁷

SRRM2 is associated with:

• Status epilepticus
• Chondromalacia of the Patella

Related signal paths:

• Processing of Pre-mRNA Containing Capped Introns
• RNA binding
• C2H2-zinc-finger domain binding

Paralog: MUC12

SRRM2 gene variants with loss of function share the following clinical features:⁹⁸⁹⁹

• Developmental delay
  • to varying degrees
  • A link to SRRM2 was found in 0.3% of all people with ADHD
• ADHD
  • ADHD symptoms in 8 of 22 people with ADHD⁹⁹
• Autism
• Macrocephaly
• Hypotension
• gastroesophageal reflux
• Overweight/Obesity

1.17. DMD, dystrophinopathy, muscular dystrophy, muscle weakness (up to 32%)¶

Dystrophinopathies are monogenic disorders of the DMD gene on the X chromosome, which is why only boys are affected.
The prevalence of Duchenne muscular dystrophy in the general population is 1 in 3,500 to 6,000¹⁰⁰, while the prevalence of Becker muscular dystrophy is 1 in 16,700 to 18,500¹⁰¹.

In cases of dystrophinopathy (such as Duchenne muscular dystrophy—complete absence of dystrophin in muscle tissue ¹⁰² or Becker muscular dystrophy —insufficient dystrophin levels¹⁰³ ), there was evidence of a significantly increased prevalence of ADHD¹⁰⁴ ranging from 18.4%¹⁰⁵¹⁰⁶ to 11.7%¹⁰⁷ and 9.8% in Duchenne ¹⁰⁸, and of ASD ranging from 6%¹⁰⁵ to 12.73%¹⁰⁶ (4.2% for Duchenne¹⁰⁸ ) and 22% for intellectual disability.¹⁰⁵
Hyperactivity and/or inattention were found in 31.4% of people with ADHD.¹⁰⁹
Hyperactivity was observed in 24% of people with Duchenne muscular dystrophy.¹¹⁰
Inattention was observed in 44% of people with Duchenne muscular dystrophy.¹¹⁰
Internalizing problems were found in 24% of people with ADHD.¹¹⁰
Externalizing problems were found in 15% of people with Duchenne muscular dystrophy.¹¹⁰
Emotional and/or behavioral problems were found in 38.7% of people with Duchenne muscular dystrophy.¹⁰⁹
A review reports an ADHD risk in Duchenne patients ranging from 11% to 32%, compared to 6% to 7% in the general population, representing an 83% to 357% increased risk of ADHD.¹¹¹
A study found only one case of ADHD among 36 people with Duchenne muscular dystrophy and one person with Becker muscular dystrophy.¹¹²

1.18. NSD1, Sotos syndrome (31.7%)¶

Sotos syndrome results from a mutation in the NSD1 gene and occurs de novo in 95% of cases. Its prevalence is 1 in 14,000 births.

Symptoms:¹¹³

• prenatal macrosomia
• postnatal tall stature
• Macrosomia (infant’s weight above the 95th percentile, 4,350 g)
• excessive growth during the first 5 years of life, especially during the 2nd and 3rd years
• morphological bone age higher than actual age
• muscular hypotonia
• Dolichocephaly (elongated skull, excessive longitudinal growth of the skull)
• facial dysmorphisms
• Hypertelorism
• thinning hair, receding hairline
• high forehead
• a long, prominent chin
• Orthopedic problems (e.g., scoliosis, foot deformities)
• Developmental disorders (of varying severity)
  • motor
  • cognitive
  • linguistic
• ADHD prevalence: Total 31.7% (13/41)
  • 53.8% (7/13)¹¹⁴
  • 21% (6/28)¹¹⁵
• ASD prevalence: Total 29.3% (12/41)
  • 30.8% (4/13)¹¹⁴
  • 28.5% (8/28) ¹¹⁵

1.19. MEFV, Familial Mediterranean Fever, FMF (31%)¶

The prevalence of familial Mediterranean fever (FMF) worldwide is 1 in 20,000.
Among people from the eastern Mediterranean region of Armenian, Turkish, Arab, or Sephardic Jewish descent, the prevalence of FMF ranges from 1 in 200 to 1 in 1,000 (approximately 0.5% to 0.01%), which is 20 to 100 times higher than elsewhere.
The prevalence of ADHD in FMF is approximately 31% (METASTUDY, k = 36, n = 907)¹¹⁶. Individual studies found a prevalence of 32.8%¹¹⁷ or 28%¹¹⁸.

FMF is a rare, hereditary autoinflammatory disorder caused by monogenic autosomal-recessive mutations in the MEFV gene.
The mutations cause the pyrin protein to malfunction. Pyrin regulates the inflammatory response.
Symptoms:

• Recurrent episodes of fever, abdominal pain, chest pain, and joint pain caused by inflammation of the serous membranes (peritoneum, pleura)
• Episodes are usually brief (1–3 days)
• Frequency of episodes: every 4 weeks to once a year
  • often completely symptom-free in between

Comorbidities:

• Headaches (42.9%)
• Muscle weakness, diplopia (35.7%)
• Sensory disturbances (35.7%)
• Facial nerve palsy (14.3%)
• Multiple sclerosis (28.6%).
• ADHD (31%)

Treatment:

• Colchicine to control flare-ups and prevent the serious complication of amyloidosis

1.20. ZMIZ1 loss of function (20% to 28%)¶

A study reports an ADHD prevalence among people with ADHD who have loss-of-function variants of the ZMIZ1 gene (Zinc Finger MIZ-Type Containing 1) of:¹¹⁹

• TRP domain: 20% (ASS: 60%)
• Proline-rich domain: 22% (67%)
• Alanine-rich domain: 28% (14%)

The percentages were calculated from the chart provided.

ZMIZ1 is a chromatin remodeler and transcription activator.¹¹⁹
Among other things, ZMIZ1 regulates

• Embryonic development
• Angiogenesis
• Immune response

1.21. MBOAT7 encephalopathy (26.6%?)¶

Of the 15 people with MBOAT7 encephalopathy, 4 had attention problems (26.6%).¹²⁰
MBOAT7 encephalopathy is associated with neurodevelopmental disorders, intellectual disability, epilepsy, and neuropsychiatric disorders such as ADHD and ASD.

1.22. BSN, Bassoon (25%)¶

The prevalence of de novo BSN variants is unknown.

Of the 29 people with ADHD who are affected by a de novo variant of BSN—which encodes the presynaptic protein Bassoon—the following were observed:¹²¹

• 49% epilepsy
• 38% developmental delay
• 34% obesity
• 28% speech delay
• 25% ADHD
• 17% ASS

1.23. FOLR1, Cerebral Folate Transporter Deficiency (22.2% ?)¶

Of the 9 people with ADHD identified, 2 had ADHD (22.2%).¹²²
The first noticeable symptoms were febrile seizures and ADHD symptoms. 44.4% suffered from ataxia and neuromotor and intellectual disabilities,

1.24. CFTR, CNFTR, cystic fibrosis (5.26% to 21.9%)¶

Other names: Ciliary Neurotrophic Factor Receptor Gene; CF Transmembrane Conductance Regulator; DJ760C5.1; TNR-CFTR; CFTR/MRP; ABC35; ABCC7; MRP7; Cystic Fibrosis Transmembrane Conductance Regulator; Channel Conductance-Controlling ATPase; CAMP-Dependent Chloride Channel; CF; Cystic Fibrosis Transmembrane Conductance Regulator, ATP-Binding Cassette (Subfamily C, Member 7); Cystic Fibrosis Transmembrane Conductance Regulator (ATP-Binding Cassette Subfamily C, Member 7); Cystic Fibrosis Transmembrane Conductance Regulator; ATP-Binding Cassette Subfamily C, Member 7; ATP-Binding Cassette Subfamily C Member 7; EC 3.6.3.49; EC 5.6.1.6; EC 3.6.3

A CFTR gene dysfunction is estimated to occur in 3 to 4% of the population, or in 1 out of every 25 to 33 people.¹²³ Cystic fibrosis affects 1 in every 3,300 to 4,800 newborns.

Cystic fibrosis is associated with increased ADHD symptoms.¹²⁴ The reported prevalence rates of ADHD among people with cystic fibrosis ranged from 5.26% to 21.9%.¹²⁵

Cystic fibrosis is associated with mutations in the CFTR gene¹²⁶, which has been identified as a candidate gene for ADHD.^127124128
CTFR-KO zebrafish exhibit ADHD symptoms such as hyperactivity, impulsivity, and attention problems.¹²⁹

The CFTR protein encodes a member of the ATP-binding cassette (ABC) transporter superfamily. CFTR functions as a chloride channel—a feature that makes it unique among the members of this protein family—and regulates the secretion and absorption of ions and water in epithelial tissues. Channel activation is mediated by cycles of phosphorylation of the regulatory domain, ATP binding by the nucleotide-binding domains, and ATP hydrolysis. The cystic fibrosis transmembrane conductance regulator (CFTR) is a protein located on the surface of cells, known as a chloride channel. Mutations in the CFTR gene in humans lead, among other things, to the absence or impaired function of the channel, which can cause cystic fibrosis and congenital aplasia of the vas deferens (CAVD). CFTR is an epithelial ion channel that plays an important role in regulating epithelial ion and water transport, as well as fluid homeostasis (including in the airways). CFTR ( ) mediates the transport of chloride ions across the cell membrane. Chloride channels are a family of anion-selective channels involved in a variety of biological processes, including the regulation of neuronal excitability, skeletal, cardiac, and smooth muscle, the regulation of cell volume, transepithelial salt transport, and the acidification of intracellular and extracellular compartments. CFTR channel activity is coupled to ATP hydrolysis. The ion channel is also permeable to HCO(3)(-); its selectivity depends on the extracellular chloride concentration. CFTR also exerts its function by modulating the activity of other ion channels and transporters. CFTR contributes to the regulation of the pH and ion content of the surface fluid layer of the airways and thus plays an important role in defending against pathogens. CFTR modulates the activity of the epithelial sodium channel (ENaC) complex, in part by regulating the cell-surface expression of the ENaC complex. CFTR inhibits the activity of the ENaC channel containing the subunits SCNN1A, SCNN1B, and SCNN1G, as well as the activity of the ENaC channel containing the subunits SCNN1D, SCNN1B, and SCNN1G; however, it does not inhibit the activity of the ENaC channel containing the subunits SCNN1A, SCNN1B, and SCNN1G. CFTR can regulate bicarbonate secretion and reabsorption in epithelial cells by regulating the SLC4A7 transporter. CFTR can inhibit the chloride channel activity of ANO1. CFTR plays a role in chloride and bicarbonate homeostasis during epididymal maturation and capacitation of sperm.¹²⁶
CFTR is associated with

• Cystic Fibrosis
  • Cystic fibrosis is associated with elevated L-dopa levels in the blood and urine.¹³⁰ This suggests a link between cystic fibrosis and dopamine metabolism. However, cystic fibrosis can have various genetic (co-)causes, so it does not necessarily imply a CFTR-related cause.
• Congenital bilateral aplasia of the vas deferens
• Cystic fibrosis
  • Cystic fibrosis is the most common fatal genetic disorder among populations of Northern European descent.
  • The most common mutation in cystic fibrosis, DeltaF508, leads to impaired folding and transport of the encoded protein. Several pseudogenes have been identified in the human genome.

Related signal paths:

• wtCFTR
• delta508-CFTR Traffic / Generic Schema (Standard and CF)
• IL-1 Family Signaling Pathways
• Enzyme binding
• PDZ domain binding

Paralog: ABCC4

OMIM: Gene encoding the ciliary neurotrophic factor receptor (CNFTR)

CFTR (CNFTR) is a candidate gene for ADHD.¹²⁷

1.25. NRXN1 Exonic Deletion (10 to 20%)¶

The prevalence of exonic NRXN1 deletions in the general Danish population was 0.07%; the prevalence of all NRXN1 deletions was 0.255%.¹³¹
An English study found a prevalence of 0.039% and 0.07%, respectively.¹³²

Exonic NRXN1 deletions correlated with

• increased risk of ADHD:
  • 4.68 times the risk of ADHD¹³³
  • 2.01 times the risk of ADHD¹³¹

Based on an ADHD prevalence of 5 to 10 percent, we estimate the risk of ADHD to be 10 to 20 percent.

Non-exonic deletions were not associated with a significantly increased risk of ADHD.¹³¹

Exonic NRXN1 deletions were also associated with a dramatically increased risk of other psychiatric disorders:

• a 20.3-fold increased risk of Tourette syndrome¹³⁴
• 9.91 times the risk of epilepsy¹³⁵
• An 8.14-fold increased risk of intellectual disability / intellectual developmental disorder¹³⁶
• 7.2 times the risk of ASS¹³⁷
• 3.05 times the risk of ADHD¹³¹
• Depression:
  • 2.01 times the risk of depression¹³⁸
  • no significantly increased risk of schizophrenia¹³¹
• no significantly increased risk of schizophrenia¹³¹

1.26. ANKRD17, Ankyrin Repeat Domain Containing 17¶

Other names: Ankyrin Repeat Domain 17; GTAR; KIAA0697; NY-BR-16; MASK2; Serologically Defined Breast Cancer Antigen NY-BR-16; Ankyrin Repeat Domain-Containing Protein 17; Gene Trap Ankyrin Repeat Protein; FLJ22206; CAGS
To date, 33 people with ADHD have been identified worldwide.¹³⁹

ANKRD17 is associated with:

• ANKRD17-related neurodevelopmental syndrome¹⁴⁰
  • Developmental delays, particularly in speech
  • characterized by a variable degree of intellectual disability
  • Additional features:
    • ASS
    • ADHD
    • ophthalmic abnormalities (strabismus, refractive errors)
    • Growth disorders
    • Feeding difficulties
    • recurrent infections
    • Gait and/or balance disorders
    • Epilepsy
  • Characteristic craniofacial features:
    • triangular face shape
    • high hairline
    • deep-set and/or almond-shaped eyes with periorbital fullness
    • low-set ears
    • thick nostrils
    • flared nostrils
    • full cheeks
    • a thin line of vermilion on the upper lip
    • less common
      • Cleft palates with Pierre Robin sequence
      • Renal agenesis
      • Scoliosis.
• Chopra-Amiel-Gordon syndrome
• nonspecific syndromic intellectual disabilities
• KBG syndrome
  • KBG is a rare syndrome. Genetic variants in the ankyrin repeat domain 17 (ANKRD17), ANKDR 11 , and deletions in 16q24.3 can cause KBG syndrome.
  • For more information on KBG syndrome, see ANKRD11, Ankyrin Repeat Domain Containing 11

1.27. KMT2B, Lysine Methyltransferase 2B¶

Other names: MLL2; TRX2; HRX2; WBP7; MLL4; Histone Lysine N-Methyltransferase 2B; KIAA0304; CXXC10; MLL1B; Myeloid/Lymphoid or Mixed-Lineage Leukemia (Trithorax Homolog, Drosophila) 4; Myeloid/Lymphoid or Mixed-Lineage Leukemia Protein 4; Lysine (K)-Specific Methyltransferase 2B; WBP-7; Histone Lysine N-Methyltransferase MLL4; Mixed Lineage Leukemia Gene Homolog; Lysine N-Methyltransferase 2B; WW Domain-Binding Protein 7; WW Domain-Binding Protein 7; Trithorax Homologue 2; Trithorax Homolog 2; EC 2.1.1.364; DYT28; MRD68

The KMT2B protein contains several domains, including a CXXC zinc finger, three PHD zinc fingers, two FY-rich domains, and a SET domain (Suppressor of Variegation, Enhancer of Zeste, and Trithorax). The SET domain is a conserved C-terminal domain characteristic of proteins in the MLL (mixed-lineage leukemia) family. The KMT2B gene is ubiquitously expressed in adult tissues. It is also amplified in solid tumor cell lines.
KMT2B is a histone methyltransferase that catalyzes the transfer of a methyl group from S-adenosyl-L-methionine to the epsilon-amino group of Lys-4“ on histone H3 (H3K4) via a non-processive mechanism. As part of the chromatin remodeling machinery, it primarily forms H3K4me1 and H3K4me2 methylation marks at active chromatin sites where transcription and DNA repair occur. KMT2B likely plays a redundant role with KMT2C in the enrichment of H3K4me1 marks on primed and active enhancer elements. KMT2B plays a central role in regulating transcription of the beta-globin locus by being recruited by NFE2. KMT2B plays an important role in controlling H3K4me levels during oocyte growth and preimplantation development. KMT2B is required during the transcriptionally active period of oocyte growth for the establishment and/or maintenance of H3K4 trimethylation (H3K4me3), a form of global transcriptional silencing that precedes the resumption of meiosis, oocyte survival, and normal activation of the zygotic genome.¹⁴¹
KMT2B is associated with

• intellectual developmental disorder, autosomal dominant 68
• Tumor (possibly)
• Dystonia 28, onset in childhood
  KMT2B-related dystonia is associated with symptoms of ADHD.¹⁴²
  • Gene variants that can cause what is known as “KMT2B-related dystonia” include:
    • a heterozygous pathogenic variant in KMT2B or
    • has a heterozygous interstitial deletion of 19q13.12 that includes a full-length KMTB2 gene deletion
  • KMT2B-related dystonia is a very rare disorder. To date, 39 people with ADHD have been reported.
  • Dystonia usually begins within the first ten years of life, but it can also occur in the second decade or later
  • First impression:
    • Most commonly, dystonia of the lower extremities, manifesting as:
      • Walking on tiptoes
      • abnormal gait
      • Balance disorders
    • Less common:
      • Dystonia of the upper limbs
      • cervical or trunk dystonia
  • As we get older:
    • severe cervical, laryngeal, and/or cranial dystonia, manifesting as
      • Retrokollis
      • Torticollis
      • Dysarthria/anarthria
      • Dysphonia
      • Difficulty swallowing and chewing
  • Within two to 11 years after onset: progression to generalized dystonia
  • KMT2B-related dystonia is associated with ADHD symptoms.

Related signal paths:

• PKMTs methylate histone lysines
• Gene expression (transcription)
• DNA-binding transcription factor activity
• Histone methyltransferase activity (H3-K4-specific)

Paralog: KMT2A

KMT2B-related dystonia is associated with ADHD symptoms.¹⁴²¹⁴³

1.28. H1-4, Rahman Syndrome¶

Other names: H1.4 Linker Histone, Cluster Member; HIST1H1E; H1s-4; H1.4; H1F4; Histone Cluster 1 H1 Family Member E; H1 Histone Family, Member 4; Histone Cluster 1, H1e; Histone 1, H1e; Histone H1s-4; Histone H1.4; Histone H1b; H1e; DJ221C16.5; RMNS; H1E

H1-4 encodes a protein. The histone H1 protein binds to the linker DNA between nucleosomes and forms the chromatin fiber. Histone H1 is necessary for the condensation of nucleosome chains into higher-order fibers. It also acts as a regulator of individual gene transcription through chromatin remodeling, nucleosome spacing, and DNA methylation.¹⁴⁴

H1-4 is associated with

• Hist1h1e syndrome (Rahman syndrome)¹⁴⁵
  • Intellectual disability (mild to severe) (100%)
  • Abnormal brain MRI (92%)
    • in particular, anomalies of the corpus callosum
  • Cryptorchidism (75%)
  • Hypotension (67%)
  • Behavioral problems (59%)
    • Anxiety, Phobias
    • compulsive behavior
    • ADHD
    • Aggression
    • auditory hypersensitivity
    • Symptoms of AS
  • Skeletal features (54%)
  • Abnormal dentition (51%)
    • Crumbling teeth
    • missing teeth
    • multiple cavities
  • Congenital heart defects / Abnormal echocardiogram (40%)
    • Atrial septal defect is the most common
  • Hypothyroidism (29%)
  • delayed motor development

Related signal paths:

• cellular responses to stimuli
• programmed cell death

Paralog: H1-5

1.29. SATB2¶

SATB2-associated syndrome (SAS) is a multisystem disorder characterized by developmental delay or intellectual disability.
Causes: de novo occurrence of:¹⁴⁶

• heterozygous intragenic pathogenic SATB2 variant
• heterozygous non-recurrent deletion at 2q33.1, which includes SATB2
• Chromosomal translocation or inversion with a breakpoint at 2q33.1 that disrupts SATB2
• chromosomal duplication with breakpoints that include SATB2.

Symptoms:¹⁴⁶

• Speech delay and/or absence of speech (in all people with ADHD)
• a cheerful or friendly personality
• autistic tendencies
  - Restlessness or aggressive outbursts
• Self-harm
  - Impulsivity
  - Hyperactivity
• Anxiety
• Difficulty falling asleep and staying asleep
• sensory issues
• Hypotension (in most people with ADHD)
• EEG abnormalities (common)
• clinical seizures (20% of people with ADHD)
• Status epilepticus during sleep
• nonspecific dysmorphic features
• Palatal anomalies (cleft palate, high-arched palate, laryngeal insufficiency, bifid uvula)
• Dental anomalies (including abnormal shape or size of the upper central incisors, overjet, hypodontia, and delayed tooth eruption)
• Skeletal abnormalities (scoliosis, tibial deformity, and joint contractures)
• Broken bones (one in three)
• low bone mineral density (one in four)
• prenatal and postnatal growth disorders
• Nutritional problems
• Eye abnormalities (strabismus, refractive errors)
• cardiovascular, genitourinary, and ectodermal findings

1.30. ODC1, ornithine decarboxylase 1, Bachmann-Bupp syndrome, BABS¶

Other names: ODC; Ornithine Decarboxylase; EC 4.1.1.17; NEDBIA; NEDBA; BABS

The enzyme ODC1 catalyzes the first and rate-limiting step of polyamine biosynthesis, converting ornithine to putrescine, which is the precursor to the polyamines spermidine and spermine. Polyamines are essential for cell proliferation and play a role in cellular processes ranging from DNA replication to apoptosis. The activity level of the ODC1 enzyme varies in response to growth-promoting stimuli and exhibits a high turnover rate compared to other mammalian proteins. Originally, the gene encoding this enzyme was localized to both chromosome 2 and chromosome 7. It has since been determined that it is located at 2p25, with a pseudogene located at 7q31-qter.¹⁴⁷
ODC1 is associated with:

• Sleeping sickness
• Bachmann-Bupp syndrome
  • Bachmann-Bupp syndrome (BABS) is characterized by:¹⁴⁸
    • severe alopecia (hair loss)
    • moderate to severe global developmental delay
    • Hypotension
    • nonspecific dysmorphic features
    • Behavioral problems
      • ASS
        - ADHD
    • Feeding problems
    • Hair
      • severe alopecia (hair loss)
      • usually present at birth
      • may be sparse
      • may have an unexpected color
      • falls out in large clumps during the first few weeks of life
    • Seizures in early childhood (rare)
    • Conductive hearing loss (rare)

Abnormal metabolites of polyamine metabolism (including elevated N-acetylputrescine levels) are indicative of BABS.
Diagnosis through molecular genetic testing for a heterozygous pathogenic de novo variant of the ODC1 gene.

Related signaling pathways:

• L-Methionine Salvage Cycle III
• Regulation of activated PAK-2p34 through proteasome-mediated degradation
• Protein homodimerization activity
• Ornithine decarboxylase activity

Paralog: AZIN2

1.31. CYP27A1, Cerebrotendinous xanthomatosis, CTX¶

Cerebrotendinous xanthomatosis is a rare genetic disorder (prevalence 1 in 70,000) of the CYP27A1 gene that is inherited in an autosomal recessive manner. CTX is often not diagnosed until early adulthood, when neurological symptoms become apparent.¹⁴⁹
CTX includes:¹⁵⁰

• Impaired lipid storage
• Altered bile acid biosynthesis pathways
• Cholesterol metabolites (e.g., cholestanol) are elevated in
  • Tissue
  • Brain
  • Eye lens
  • Tendons

Symptoms:¹⁵⁰

• progressive neurological problems (64–92%)
  • Spasticity
  • Pyramidal signs
• neuropsychiatric symptoms
  • cognitive impairments (87%)
  • Behavioral disorders
• juvenile cataracts (82%)
• Xanthomas (yellowish/orange fatty deposits)
  • Tendon xanthomas (76%)
• Osteoporosis (65%)
• chronic diarrhea (31%)
• psychiatric disorders (11.4%)
• Cardiovascular diseases

Cerebrotendinous xanthomatosis may be associated with ADHD symptoms.¹⁵¹¹⁵⁰

1.32. SMAD4, Myhre¶

Other names: SMAD Family Member 4; DPC4; MADH4; Mothers Against Decapentaplegic Homolog 4; Deletion Target in Pancreatic Carcinoma 4; MAD Homolog 4; MAD, Mothers Against Decapentaplegic Homolog 4 (Drosophila); Mothers Against Decapentaplegic, Drosophila, Homolog of, 4; SMAD, Mothers Against DPP Homolog 4 (Drosophila); Deleted in Pancreatic Carcinoma Locus 4; SMAD, Mothers Against DPP Homolog 4; Mothers Against DPP Homolog 4; SMAD 4; HSMAD4; MYHRS; Smad4; JIP¹⁵²

Associated with:

• Myhre syndrome
  • Since its discovery in 1981, only 300 cases of Myhre have been identified worldwide¹⁵³
• juvenile polyposis syndrome

Connected signal paths:

• Autolysis of the E3 ubiquitin ligase COP1
• Gene expression (transcription)
• DNA-binding transcription factor activity
• sequence-specific DNA binding

Paralog: SMAD2

Myhre is associated with an increased prevalence of ADHD and ASD.¹⁵³

Symptoms of Myhre syndrome:¹⁵³

• Joint stiffness
• restrictive lung and cardiovascular diseases
• progressive and proliferative fibrosis
• Thickening of the skin
• recurrent infections (including middle ear infections, sinusitis, mastoiditis, and croup)
• Hearing loss (progressive)
• Growth impaired at an early stage
• Obesity in Adolescence
• Refractive errors
• Astigmatism
• Korrektopia
• Abnormalities of the optic nerve
• gastroesophageal reflux disease
• Constipation
• Encopresis
• Strictures of the gastrointestinal tract (less common)
• Hirschsprung’s disease (less common)
  • Hirschsprung’s disease appears to be associated with an increased prevalence of ADHD¹⁵⁴
• metabolic dysfunction of the liver (less common)

Traumas can trigger:¹⁵³

• abnormal scarring
• Adhesions
• invasive medical procedures / surgeries
• Effusions in the heart, airways, lungs, uterus, or peritoneum that can progress to fibrosis

Characteristic facial features in most people with ADHD:¹⁵³

• narrow eye slits
• deep-set eyes
• Underdevelopment of the upper jaw
• short philtrum
• thin upper lip
• narrow mouth
• Prognathism

Neurological symptoms:¹⁵³

• Developmental delays (usually mild to moderate)
• cognitive impairments (usually mild to moderate)
• ASS
• ADHD
• Anxiety

1.33. SETD5¶

Pathogenic variants in the SETD5 gene cause:¹⁵⁵

• Hypotension (39.2%)
• hyperkinetic movement disorders, including stereotypies and chorea (21.4%)
• Gait disorders (35.7%)
  • Walking on tiptoes
  • unsteady gait
  • Changes in fine motor skills
• Epilepsy (14%)
  • epileptic spasms
  • focal motor and non-motor seizures
• mild to severe intellectual disability or global developmental delay (75%)
• borderline intellectual functioning (21.4%)
• ASS
• ADHD
• psychotic disorders
• other internalizing and externalizing symptoms

1.34. RUNX1T1¶

The Runt-related transcription factor 1, which has been translocated to chromosome 1 (RUNX1T1; also known as Eight-Twenty-One [ETO]), encodes a transcriptional regulator of hematopoietic genes and is known for its involvement in hematologic malignancies, particularly acute myeloid leukemia (AML).
RUNX1T1 de novo alterations were observed:¹⁵⁶

• craniofacial dysmorphisms
• neurodevelopmental disorders, including
  • Developmental delays
  • Learning Disabilities
  • ADHD
  • ASS

1.35. ARID1B haploinsufficiency¶

ARID1B haploinsufficiency is estimated to occur in 1 in 10,000 to 1 in 100,000 people (0.01 to 0.001% of the population).¹⁵⁷

ARID1B-associated disorder (ARID1B-RD) represents a clinical continuum. This ranges from classic Coffin-Siris syndrome to intellectual disability with or without nonspecific dysmorphic features:¹⁵⁸

• Aplasia or hypoplasia of the distal phalanx or nail of the fifth and subsequent fingers
• Developmental or cognitive delays of varying degrees
• distinctive facial features
• Hypotension
• Hypertrichosis
• thinning hair
• Developmental delays
  • Language development is often more advanced than motor development)
  • Heart defects
  • Malformations of the gastrointestinal tract
  • Malformations of the urogenital system
  • Malformations of the central nervous system
• Feeding difficulties
• slow growth
• ophthalmic abnormalities
• Hearing impairments
• Seizures
• ADHD
• ASS

1.36. Congenital disorder of glycosylation (CDG)¶

To date, there have been only a few cases in which abnormal glycosylation (congenital disorder of glycosylation, CDG) has been linked to ADHD:¹⁵⁹

• Alpha-1,3-glucosyltransferase (ALG8) CDG is characterized by musculoskeletal, dermatological, and cardiac symptoms, as well as intellectual disabilities¹⁶⁰
• People with ADHD showed
• increased levels of biantennary glycans with antenna fucose (A2FG2) and decreased levels of tri- and tetra-antennary glycans.¹⁶¹¹⁶²
• reduced α2-3 sialylation¹⁶²
• One case of CDG with preserved oligomeric Golgi (COG) presented with ADHD.¹⁶³

CDG has already been described in connection with other neurodevelopmental disorders, such as autism.
Additional N-glycosylation abnormalities have been described in ADHD. In people with ADHD, the following were found:

Similarly, a link was found with ASD, ataxia, and other conditions that occur more frequently in ADHD,¹⁶⁴

A lack of N-linked glycosylation can impair the membrane localization of D5R (but not D1R)¹⁶⁵. D5R plays a role in ADHD.
Contradictory glycosylation of the dopamine transporter (DAT) leads to more efficient dopamine transport (which is the classic pathway for ADHD) and is discussed as a possible mechanism underlying the vulnerability of midbrain dopamine neurons in Parkinson’s disease.¹⁶⁶

1.36.1. Transferrin, TF¶

A case study reports on a young woman with a heterozygous transferrin mutation c.1295 A > G, which disrupts the glycosylation site at asparagine 432. As a result, the people with ADHD’s transferrin has only a single glycosylation site, and the hypoglycosylation is not indicative of a CDG disorder. They had ADHD.¹⁵⁹ MPH caused side effects, while lisdexamfetamine alleviated the ADHD symptoms without causing side effects. The case study suggests a possible monogenic cause of ADHD due to transferrin mutations.

1.36.2. STT3A, STT3 Oligosaccharyltransferase Complex Catalytic Subunit A¶

Other names: STT3-A, TMC, Integral Membrane Protein 1, ITM1, Dolichyl-Diphosphooligosaccharide-Protein Glycosyltransferase Subunit STT3A, STT3A, Catalytic Subunit of the Oligosaccharyltransferase Complex, Dolichyl-Diphosphooligosaccharide Protein Glycosyltransferase, Oligosaccharyl Transferase Subunit STT3A, Transmembrane Protein TMC

The STT3A protein is a catalytic subunit of the N-oligosaccharyltransferase (OST) complex, which transfers glycan chains to asparagine residues on target proteins in the endoplasmic reticulum. It is associated with CFTR activation by S-nitrosoglutathione (in both healthy and cystic fibrosis patients) and the translation of structural proteins.
STT3A is associated with

• Congenital glycosylation disorder, type Iw, autosomal recessive
• Congenital glycosylation disorder, type Iw, autosomal dominant

Given the influence of STT3A on N-glycosylation, we assume that its mechanism of action on the dopaminergic system is similar to that of 1.105. MAN2A2.

A study identified STT3A as one of the 51 most likely genetic candidates for ADHD.⁵⁶

Congenital dysglycosylation (CDG) type Iw (OMIM# 619714), An autosomal dominant disorder, is caused by a heterozygous mutation in the STT3A gene. Most CDGs are inherited in an autosomal recessive (AR) manner; however, several cases with an autosomal dominant (AD) form of an AR CDG have recently been identified.
A case study describes a 17-year-old male with macrocephaly, failure to thrive, short stature, epilepsy, ASD, ADHD, mild developmental delay, intermittent hypotension, dysmorphic features, and a mildly enlarged aortic root with a previously unreported de novo STT3A variant (c.1631A > G: p.Asn544Ser). This variant deletes a glycosylation site and was predicted to be destabilizing by structural biology modeling. The metabolomic profile indicates an abnormal transferrin profile consistent with CDG type Iw. The phenotypic, molecular, and metabolic findings were consistent with CDG type Iw due to a heterozygous STT3A variant.¹⁶⁷

1.36.3. COG6¶

There are two known Swedish cases of congenital glycosylation disorders involving conserved oligomeric Golgi complex subunit 6 (COG6-CDG).
One of them was diagnosed with ADHD at 4 years and 9 months of age. The other has not (yet) been diagnosed with ADHD at 3.5 years of age.
Additional clinical symptoms included intellectual disability, delayed myelination of the brain, progressive microcephaly, joint laxity, hyperkeratosis, frequent infections, and enamel hypoplasia. In one family, compound heterozygous variants in COG6 were identified: c.785A>G; p.Tyr262Cys and c.238G>A; p.Glu80Lys. In addition, a previously undescribed homozygous duplication (c.1793_1795dup) was considered the cause of the disorder. The cells of people with ADHD exhibit significantly slower anterograde and retrograde ER-Golgi transport.¹⁶³

1.37. PTS-related tetrahydrobiopterin deficiency, PTPSD¶

The exact prevalence of PTPSD is unknown.
The prevalence of all forms of BH4 deficiency is estimated to be between 1 in 75,000 and 1 in 150,000. PTPSD accounts for approximately 54% of all BH4 deficiency conditions, suggesting a PTPSD prevalence of 1 in 150,000 to 1 in 300,000.¹⁶⁸

PTS-associated tetrahydrobiopterin deficiency (PTPSD) is a monogenic disorder.
Tetrahydropterin is an important cofactor for the synthesis of phenylalanine hydroxylase (PAH), tyrosine hydroxylase, and tryptophan hydroxylase.

PTPSD is inherited in an autosomal recessive pattern.¹⁶⁸
If both parents are known to be heterozygous for a pathogenic PTS variant, each sibling of a person with ADHD has a probability at conception of

• 25% are also affected
• 50% chance of being an asymptomatic carrier
• 25% chance of not inheriting any of the familial pathogenic PTS variants

If one parent has PTPSD and the other has two normal PTS alleles, the children are obligate heterozygotes. If the mother is the person with ADHD, MPKU syndrome is a critical factor.¹⁶⁸

PTPSD is associated with an increased risk of ADHD.¹⁶⁸ The prevalence of ADHD is unknown.

1.38. Glucose-6-phosphate dehydrogenase deficiency (G6PD)¶

Glucose-6-phosphate dehydrogenase (G6PD) deficiency increased the risk of ADHD by 16%.¹⁶⁹

G6PD deficiency is the most common enzyme deficiency worldwide. It results from an X-linked genetic Disorder and affects approximately 4.9% of the global population. Since G6PD deficiency offers some protection against malaria, it is geographically more common in areas where malaria occurs. The prevalence in Germany is less than 1%.
The enzyme glucose-6-phosphate dehydrogenase (G6PD) facilitates the synthesis of nicotinamide adenine dinucleotide phosphate (NADPH) and glutathione (GSH), which are involved in regulating the redox balance. G6PD deficiency leads to reduced GSH levels and, consequently, increased oxidative stress.

Types of defects:¹⁷⁰

• Fault Type A
  • G6PD residual activity of 5 to 15% of normal
  • Common in Southern Europe, West Africa, and among the African American population in the U.S.
• Mediterranean Defect Variant
  • G6PD residual activity below 1% of normal
  • Common in Mediterranean coastal regions, the Middle East, and India
• G6PD Vianchan and G6PD Mahidol: Southeast Asia
• G6PD Canton: China
• G6PD Union: Worldwide

G6PD deficiency is usually food-related (favism; a hemolytic reaction to the consumption of fava beans) and is sometimes genetic (common in the Mediterranean region and the Middle East, and to some extent in Asia and Africa).
G6PD deficiency can cause (especially in children):

• severe hemolysis
• Hyperbilirubinemia
• Jaundice
• Hearing impairments
• Behavioral disorders
• long-term neurological damage
• increased production of reactive oxygen species (ROS)
  • resulting in the activation of astrocytes and microglia, increased levels of proinflammatory chemokines and cytokines, neuroinflammation, and impaired brain development
• Imbalance in the antioxidant system
  • which leads to damage to astrocytes, neuronal death, and DNA damage
  • oxidative cell death of leukocytes, myocytes, and other immune cells.

1.39. Creatine Deficiency Disorders¶

Creatine deficiency disorders are rare monogenic disorders. To date, 130 people with ADHD have been reported worldwide.
Genetic Counseling.
Creatine deficiency disorders can result from¹⁷¹

• GAMT deficiency caused by a pathogenic variant in the GAMT gene, inherited in an autosomal recessive manner
• AGAT deficiency caused by a pathogenic variant in the GATM gene, inherited in an autosomal recessive manner
• CRTR deficiency caused by a pathogenic variant in the SLC6A8 gene, inherited in an X-linked manner

Creatine deficiency disorders are associated with an increased risk of ADHD.¹⁷¹

1.40. Arginine succinate lyase deficiency (ASLD)¶

Arginine succinate lyase deficiency (ASLD, arginine succinate disease) is a congenital disorder of urea synthesis. ASLD can present as a neonatal or late-onset disorder.
A monogenic disorder caused by mutations in the ASL gene. It is inherited in an autosomal recessive pattern (both parents must be carriers of a mutated gene for the child to develop the disorder).
Prevalence: 1 to 9 per 100,000¹⁷²

In addition to ASLD, other forms of urea cycle disorders include: ornithine transcarbamylase deficiency (OTCD), carbamoyl phosphate synthetase 1 deficiency (CPS1D); arginine succinate synthetase deficiency (ASSD), and arginase-1 deficiency (ARG1D). An increased prevalence of ADHD was found particularly in ASSD.¹⁷³

Neonatal ASLD:¹⁷⁴

• Hyperammonemia within the first few days after birth
  • Symptoms: increasing vomiting, lethargy, refusal to eat, tachypnea, and respiratory alkalosis
  • If left untreated, lethargy may worsen, leading to seizures, coma, and even death

Late-onset ASLD:¹⁷⁴

• episodic hyperammonemia caused by acute infections or stress
• with and without documented episodes of hyperammonemia:
  • cognitive impairments
  • Behavioral problems
  • Learning Disabilities

Long-term symptoms of ASLD

• Acute hyperammonemia and associated complications
• neurological and neurocognitive characteristics
  • ADHD
    • Attention problems in 50% of people with ADHD¹⁷⁵
    • ASLD impairs tyrosine hydroxylase in the nucleus coeruleus¹⁷⁵
  • intellectual and developmental disabilities
  • Learning Disabilities
  • Developmental delays in 92% of people with ADHD¹⁷⁶
• Seizures
• Motor and coordination abnormalities
• Liver diseases
  • Hepatomegaly
  • Hepatitis
  • Steatosis
  • Fibrosis
  • Cirrhosis
• Trichorrhexis nodosa (coarse, brittle hair that breaks easily)
• systemic hypertension
• Hypokalemia

1.41. ATP7B, Wilson’s disease¶

Wilson’s disease (prevalence: 1 in 30,000 people, 0.0033%) is associated with elevated copper levels.
People with Wilson’s disease exhibit symptoms that can be mistaken for ADHD.¹⁷⁷
Wilson’s disease is associated with a defect in the ATP7B gene and is characterized by excess copper.
Although dopamine β-hydroxylase, which converts dopamine to norepinephrine, is copper-dependent, it does not appear to be involved in Wilson’s disease.

Copper is considered a risk factor for ADHD. For more information, see Copper In the article “ ” (External Toxins as ADHD Risk Factors) in the section “ ” (Environmental Factors as Causes of ADHD) in the chapter “ ” (Development)

To the best of our knowledge, the prevalence of ADHD in Wilson’s disease has not yet been studied. There are only case reports.¹⁷⁸¹⁷⁹

1.42. Monoamine Neurotransmitter Disorders¶

Monoamine neurotransmitter disorders refer to genetic defects in transporters or deficiencies in precursors, cofactors, or enzymes that break down monoamines (e.g., dopamine).¹⁸⁰

Symptoms of a severe dopamine deficiency may include:¹⁸¹

• Parkinson’s
• Dystonia
• Chorea
• Oculogyric crises/ocular spasms
• Ptosis/Eyelid Muscle Weakness
• Swallowing difficulties
• myoclonic epilepsy
• Epileptic encephalopathy
• Progressive cognitive dysfunction
• Microcephaly
• Pyramid Railway Sign

Symptoms of a severe serotonin deficiency may include:¹⁸¹

• Temperature Issues
• Sweating
• Dystonia

To detect deficiencies in precursor substances and specific metabolic disorders, measuring pterines (particularly biopterin and neopterin) in urine is helpful:

*GTP Cyclohydrolase 1 Deficiency (GCH 1)

• 6-Pyruvoyl-tetrahydropterin synthase deficiency
• Dihydropteridine reductase deficiency
• Sepiapterin reductase deficiency
• Aromatic L-Amino Acid Decarboxylase Deficiency
  • 3-Ortho-methyldopa increases
  • Vanillic acid increases
• Dopamine Transporter Deficiency Syndrome (DTDS)
  • Elevated HVA-to-creatine ratio in urine
• Severe dopamine deficiency
  • Elevated prolactin levels in the blood
  • Galactorrhea
• A significant excess of dopamine
  • Reduced prolactin levels in the blood

1.42.1. Genetic BH4 Disorders¶

The prevalence of genetically caused BH4 disorders in the general population is approximately 0.0002%.
Genetic disorders of tetrahydrobiopterin synthesis (BH4, an enzyme essential for dopamine synthesis), such as

• autosomal recessive (AR) guanosine triphosphate cyclohydrolase deficiency (GTPCH deficiency)
  • Prevalence less than 1 per 1,000,000 (less than 0.0001%)¹⁸²
  • 46% of all BH4 disorders
• 6-Pyruvoyl-tetrahydropterin synthase deficiency (PTPS)
  • Prevalence: 1 in 500,000 to 1 in 1,000,000 (0.0001% to 0.0002%) ¹⁸³
  • 54% of all BH4 disorders
  • See above for more on this

appear to contribute to ADHD and other mental disorders such as anxiety, depression, aggression, or oppositional defiant behavior.¹⁸⁴

See also tyrosine hydroxylase In the article Dopamine Synthesis.

1.42.2. Missing or significantly reduced DAT¶

There are (rare) individuals with no DAT or with a very significantly reduced DAT. However, these individuals exhibit additional symptoms that are not typical of ADHD (e.g., early-onset Parkinsonian dystonia) and are therefore rarely misdiagnosed with ADHD; instead, they are more often misdiagnosed with cerebral palsy. Many people with ADHD die as early as their teenage years.¹⁸⁵ An excess of extracellular dopamine leads, through the activation of presynaptic D2 autoreceptors, to reduced dopamine production (and thus to reduced dopamine storage in vesicles) as well as to downregulation or desensitization of dopamine receptors, resulting in a deficiency of phasic dopamine and a lack of dopamine efficacy.¹⁸⁰

2. Monogenetic Animal Models for ADHD Symptoms¶

Animal models are used to study the effects of individual genes that have been knocked out or overexpressed. Since, in the vast majority of cases, only a single gene is modified, the effects of that individual gene can be readily determined by comparing it to the same mouse strain without the genetic modification.
Cabana-Domínguez et al. compiled a review of 161 mouse models in which the manipulation of individual genes triggered hyperactivity, hyper- and hypoactivity, impulsivity, or inattention.¹⁸⁶

2.1. Monogenetic Causes of Hyperactivity¶

Cabana-Domínguez et al. identified 146 mouse models in which manipulation of the following genes triggered hyperactivity.¹⁸⁶ Additional mouse models are listed with individual source citations.

• ABCA2
• ABCG1
• ACTL6B
• ADCY3
• ADCYAP1
• ADIPOR2
• ANKFN1
• ANKS1B
• AP3B2
• AP3B2
• AP3D1
• APAF1
• APP
• ARRDC3
• ARSA
• ATF2
• ATP1A3
• ATRN
• BDNF
• CACNA2D3
• CACNA2D4
• CACNG2
• CADM1
• CALM1
• CAMK2A
• CDH23
• CDK17
• CDK5R1
• CDKL5
• CELF4
• CHD3
• CHD7
• CHRD
• CHRM1
• CHRM4
• CIC
• CKAP5
• CLIC5
• CNTNAP2
• CREBBP
• DGAT1
• DGKB
• DISC1
• DNAJB5
• DRD1
• DRD2
• DRD3
• DTNBP1
• DUSP18
• EEF1B2
• ELMOD3
• EN2
• EPS15L1
• ESPN
• ESR1
• FMR1
• FOS
• FOXI1
• FXR2
• GABRA1
• GABRA3
• GABRB3
• GIT1
• GLRA1
• GNAI2
• GNAO1
• GPR135
• GPR88
• GRIA1
• GRID2
• GRIN2B
• HMOX1
• HTR2C
• HTT
• IGSF9B
• IL6
• INTS3
• KCNA4
• KCNE1
• KPNA4¹⁸⁷
  • But not KPNA3¹⁸⁷
• LDLR
• LMX1A
• LRRK2
• MAGI2
• MAOB
• MAPK3
• MAPT
• MCOLN3
• MYO6
• MYO7A
• NCOR1
• NLGN2
• NLGN3
• NOX3
• NPAS3
• NPC1
• NR4A2
• NR4A3
• NUP153
• OPRD1
• OTC
• OTOG
• PER1
• PITX3
• PKD2L2
• PNPLA6
• POU4F3
• PPARGC1A
• PPFIA3
• PPM1F
• PTCHD1
• PTPRK
• RAB5B
• RGS4
• RNF214
• RTL10
• RXYLT1
• SCN1A
• SHANK2 (see above)
• SHANK3
• SIRT1
• SLC12A6
• SLC1A2
• SLC26A10
• SLC5A7
• SLC6A3
• SLC9A6
• SNAI2
• SNCA
• SOBP
• SYNGAP1
• SYT4
• TBC1D8
• TBX10
• TECPR2
• TIP
• TMIE
• UBA6
• USH1C
• USH1G
• VIM
• VLDLR
• WDR41
• WHRN
• ZBTB20
• ZEB1
• ZPLD1

2.2. Monogenetic Causes of Hyperactivity and Hypoactivity¶

Cabana-Domínguez et al. identified six mouse models in which manipulation of the following genes triggered hyperactivity and hypoactivity:¹⁸⁶

• GPX6
• HTT
• LEPR
• PSAP
• SHANK3
• SLC6A8

2.3. Monogenetic Causes of Impulsivity¶

Cabana-Domínguez et al. identified four mouse models in which manipulation of the following genes triggered impulsivity:¹⁸⁶

• CADM1
• COMT
• PER1
• SHANK3

2.4. Monogenetic Causes of Attention Problems¶

Cabana-Domínguez et al. identified five mouse models in which manipulation of the following genes caused inattention:¹⁸⁶

• COMT
• PSEN1 (inability to sustain attention)
• PTCHD1
• SNAP25
• TARDBP (executive dysfunction)

3. Chromosomal Aberrations as Causes of ADHD¶

Chromosomal aberrations affect several or all of the genes on a chromosome and are therefore not a monogenic cause. However, they are a monocausal genetic cause, which is why we include them here.

3.1. Q11.23 deletion, Williams syndrome (64.7% to 84%)¶

Williams syndrome, also known as Williams-Beuren syndrome, occurs in 1 in 20,000 people and is caused by a microdeletion of approximately 2 million DNA base pairs from the q11.23 region of chromosome 7. This segment contains 24 genes, including the ELN gene (elastin gene), which is believed to be the primary cause of the arterial stenosis that occurs in 50% to 75% of people with Williams syndrome.¹⁸⁸ Other common features of Williams syndrome include:

• Hypercalcemia in 15% of cases
• Hypercalciuria
• Arterial calcification
• Nephrocalcinosis
• Diabetes or prediabetes
• Subclinical hypothyroidism due to a small thyroid gland
• Urogenital system defects in 20–35% of cases
  • Ectopic kidneys
  • Horseshoe Kidney
  • Bladder diverticulum
• Hypotension
• Orthopedic Problems
  • Hypermobility of the joints (Ehlers-Danlos syndrome)
    • Hyper-reflective thighs
    • Bent knees
    • Spinal Kyphosis
  • Lordosis
  • Scoliosis
• Simmband anomalies
  • Hoarse, metallic, or raspy voice¹⁸⁹
• Esophageal reflux in 25% of cases
• Intestinal Diverticula
• Chronic constipation in 50% of cases
• Chronic abdominal pain
  • Mostly due to increased anxiety symptoms
• ADHD in
  • 64.7% of 16-year-olds¹⁹⁰
  • Up to 84%¹⁸⁸
  • MPH was effective in 72.2% of cases¹⁹¹
    • Along with a significant improvement in anxiety symptoms
    • In 2/3 of cases, sadness as a side effect
• Anxiety in the form of specific phobias in 43%¹⁸⁸ to 53.8%¹⁹⁰
  • Particularly with regard to certain noises¹⁹¹
  • More generalized anxiety disorders with increasing age
• Hyperacusis in 84% of cases¹⁹²
• Intellectual Disability
  • Average IQ of 50 to 60 points (40 to 100)¹⁸⁸
  • Relative strengths:
    • Auditory memory
    • Specific language skills
    • Identification of Objects and Facial Expressions
  • Relative weaknesses
    • Spatial memory
    • Mathematics
    • Spatial-motor skills, such as orientation

3.2. Sex chromosome aneuploidy: 48,XXY; 48,XXX; 48,XYY, and 48,XXYY (up to 72%)¶

Rare Sex Chromosome Aneuploidy (SCA) Disorder
Prevalence of 48,XXYY: 1 in 18,000 to 40,000 male newborns¹⁹³

48,XXYY syndrome is considered a variant of 47,XXY Klinefelter syndrome due to a shared endocrine and physical phenotype.¹⁹⁴

Symptoms:

• tall stature (average height over 1.90 m)
• hypergonadotropic hypogonadism (testosterone deficiency)
• Infertility
• Developmental delays
• Learning Disabilities
• intellectual disabilities

Common accompanying behavioral problems include

• ADHD
  • 72%; for comparison: 36% for XXY, 52% for XXX, and 76% for XYY)¹⁹⁵¹⁹⁶
  • just under 75%¹⁹⁴
• ASS
  • up to 50%¹⁹⁴
• Anxiety
• Depression
• Sleep Disorders
• Irritability
• aggressive behavior

A study found that:¹⁹³
71% (of 101 participants, ages 4.5 to 38) were prescribed psychotropic medications, most commonly ADHD stimulants (78.9%, success rate for first medication: 43.9%), and medications for anxiety/antidepressants (60.6%, success rate for first medication: 84.2%). Subsequent attempts with medications from the same class improved the success rates per person across all medication classes, except for sleep aids and mood stabilizers.

Assuming an ADHD prevalence of 50% across all variants and an aneuploidy prevalence of 1 in 30,000, this could explain one in every 60,000 cases of ADHD in men. With an ADHD prevalence of 5%

3.3. Klinefelter syndrome (47,XXY) (25% to 63%)¶

The prevalence of Klinefelter syndrome in boys is 1 in 500 to 1 in 1,000. Only about a quarter of the people with ADHD are diagnosed, as the effects are often mild.

Klinefelter syndrome is associated with an ADHD prevalence ranging from 25% to 63%.¹⁹⁷
Klinefelter syndrome is characterized by an extra X chromosome. 63% of people with Klinefelter syndrome had ADHD, 65% had speech disorders, and 27% had ASD.¹⁹⁸

• 40% hyperactivity (n = 20) vs. 5% in the control group (n = 36)¹⁹⁹
• 55% inattention (n = 20) vs. 13% in the control group (n = 36)¹⁹⁹
  Boys with Klinefelter syndrome who did not have ADHD exhibited executive functions comparable to those of boys with Klinefelter syndrome and ADHD. It appears that Klinefelter syndrome itself is associated with executive function problems.²⁰⁰

Klinefelter syndrome is thought to correlate particularly with ADHD-I.¹⁹⁷

3.4. Trisomy 21, Down syndrome (14.6% to over 50%)¶

The prevalence of Down syndrome is reported to be 1 in 750.

Down syndrome was associated with a 1.74-fold increased risk of ADHD (14.6% overall) and a 5.4-fold increased risk of ASD (6.38% overall).²⁰¹
In special education facilities for children with Down syndrome, more than 50% are believed to also have ADHD.²⁰²
Down syndrome is associated with an increased prevalence of ASD of 39%.²⁰³

Mosaic Down syndrome is characterized by trisomy 21, which is not present in all cells. Among people with Down syndrome, 2.08% had mosaicism.²⁰⁴
Compared to unaffected individuals, people with mosaicism were more likely to

• ADHD (+26.5%; 17.7% compared to 14.0%)
• ASS (+44.8%; 13.9% compared with 9.6%)

3.5. 22Q11.2 duplication syndrome (18.2% to 44%)¶

Other names: DUP22Q11.2; Chromosome 22q11.2 Microduplication Syndrome²⁰⁵

The 22q11.2-duplication syndrome Occurs once in every 1,600 births.
22q11.2 duplication is usually inherited from the parents.
The prevalence of ADHD in individuals with 22q11.2Dup ranges from approximately 18.2% to 44%.²⁰⁶
A 22q11.2 duplication was found in 0.25 to 0.33% of people with ADHD.

Other typical symptoms include:

• Facial abnormalities
• congenital heart defects
• Immunodeficiencies
• Cleft palate
• Short stature
• Obesity
• Developmental delay

ADHD symptoms are treated according to standard protocols. A low initial dose followed by gradual up-dosing is also recommended in this case.

3.6. 22Q11.2 deletion syndrome (6% to 37%)¶

Other names: DEL22Q11.2; C22DELq11.2; C22DDELS²⁰⁷ CATCH 22, Cayler-cardiofacial syndrome, DiGeorge syndrome, DiGeorge sequence, 22q11.2 microdeletion, 22q11 monosomy, Sedlackova syndrome, Sphrintzen syndrome, conotruncal anomaly syndrome with facial dysmorphism, Takao syndrome

The prevalence of velocardiofacial syndrome is 1 to 5 per 10,000 (0.01 to 0.05%).²⁰⁸

22q11.2-deletion syndrome Occurs in one out of every 2,150 births, making it the most common deletion syndrome.
22q11.2del usually arises de novo, meaning it is not inherited from the parents.
The prevalence of ADHD in individuals with 22q11.2 deletion syndrome is elevated²⁰⁹ and ranges from about 6% to 37%.²⁰⁶²¹⁰ One study found ADHD in 2 out of 6 people with ADHD.²¹¹ People with 22q11.2 deletion syndrome (DS) have an increased risk of comorbid mental disorders such as ADHD, schizophrenia, depression, or intellectual disability.²¹² More than 85% of people with DEL22Q11.2 who had not been diagnosed with ADHD reported ADHD symptoms.²¹³

Among people with ADHD, a 22q11.2 deletion was found in 0.14% of cases.

DEL22Q11.2 is associated with

• Chromosome 22q11.2 deletion syndrome, distal
• Corneal staphyloma.

ADHD symptoms are treated according to standard protocols. A low initial dose followed by gradual up-dosing is also recommended in this case.

3.7. Turner syndrome (25%)¶

Turner syndrome is caused by the loss of part or all of the X chromosome in females.²¹⁴
Prevalence: 1 in every 2,000 to 2,500 live-born girls = 0.04% to 0.05% of the general population

Possible symptoms:^215216217

• Short stature

• dysmorphic features

• Difficulties with psychosocial adjustment

• ADHD

• Kidney and endocrine problems

• Heart defects

• Neck crease

• drooping eyelids

• increased distance between the nipples

• Infertility

• 51% in the ADHD risk range or below, among n = 49 girls with Turner syndrome²¹⁸

• 42.1% hyperactivity (n = 36) vs. 5% in the control group (n = 36)¹⁹⁹

• 42.1% inattention (n = 36) vs. 13% in the control group (n = 36)¹⁹⁹

• 26% among n = 119 women with Turner syndrome²¹⁹

  • Anxiety disorder in 26% (+225% compared to the 8% among girls in the U.S.²²⁰.)
  • Dyscalculia in 18%
  • ASS at 16%
  • a lower average nonverbal IQ (Performance Intelligence Quotient, PIQ) compared to the verbal IQ (VIQ)

• 24% among n = 50 girls with Turner syndrome, compared to 1.3% among girls in the general population. This represents an 18-fold increase in the prevalence of ADHD among girls with Turner syndrome.²¹⁵ No correlation with IQ was found.

• 13% prevalence of ADHD according to the Strengths and Difficulties Questionnaire (SDQ) among n = 100 women with Turner syndrome, compared with 0.4% prevalence of ADHD among female controls²²¹

• 13% hyperactivity (n = 40) vs. 9.9% in the control group (n = 33)²²²

• 9.4% inattention (n = 40) vs. 7.4% in the control group (n = 33)²²²

• 7% among n = 30 girls with Turner syndrome²²³

• 0% among n = 1,293 girls and women with Turner syndrome in a Swedish registry study²²⁴

ADHD symptoms included, among others:²¹⁸

• Hyperactivity (more pronounced in ADHD-HI and ADHD-C)
• Inattention
• Executive problems

Comparison of Turner Syndrome and Klinefelter Syndrome¶

Figure adapted from Greene et al., 2022.¹⁹⁹

Klinefelter syndrome (usually 47,XXY in boys) and Turner syndrome (usually 45,X0 in girls) exhibit contrasting profiles of strengths and weaknesses across many cognitive dimensions, with intelligence that is typically normal.
In healthy women (XX), one of the two X chromosomes is inactivated; however, approximately 15% of the second set of X chromosomes escapes inactivation, resulting in the expression of two copies of the gene.
In Turner syndrome, only one copy of a gene is present. This means that fewer (female) X-chromosome genes are active.
In Klinefelter syndrome (47,XXY), the genes on the extra X chromosome are not inactivated, which leads to increased expression of X-chromosome genes in addition to the normal expression of Y-chromosome genes. Consequently, a relatively greater number of female X genes are active.

Gymnasts (girls) show relatively more

• Hyperactivity/Impulsivity
• Impaired executive functions
• Weaknesses in visual-spatial skills
• Strengths in verbal skills
• Shortcomings in processing speed

Klinefelter syndrome (in boys) is relatively more common

• Inattention
• Impaired working memory
• Strengths in visual-spatial skills
• Weaknesses in verbal skills
• Weaknesses: Processing speed (unclear)
  • potentially more severe impairments in verbal information processing than in nonverbal information processing