3. Monogenetic ADHD causes

Monogenetic ADHD causes

Monogenetic causes means genes in which certain gene variants can cause disorders associated with ADHD symptoms.

1.304. ODC1, ornithine decarboxylase 1 (Bachmann-Bupp syndrome, BABS)

Other names: ODC; ornithine decarboxylase; EC 4.1.1.17; NEDBIA; NEDBA; BABS

The enzyme ODC1 ikatalyzes the first and rate-limiting step of polyamine biosynthesis, which converts ornithine to putrescine, which is the precursor for 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 enzyme ODC1 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 located on both chromosome 2 and chromosome 7. It has since been found to be localized to 2p25, with a pseudogene located on 7q31-qter.¹
ODC1 is associated with:

Sleeping sickness
Bachmann-Bupp syndrome
- Bachmann-Bupp syndrome (BABS) is characterized by:²
  - global developmental delay in the moderate to severe range
  - Hypotension
  - non-specific dysmorphic features
  - Behavioral problems
    - ASS
      ** - ADHD**
  - Feeding problems
  - Hair
    - pronounced alopecia (hairlessness)
    - usually present at birth
    - can be sparse
    - may have unexpected color
    - falls out in large clumps during the first weeks of life
  - Seizures at the beginning of later childhood (rare)
  - Conductive hearing loss (rare)
- Abnormal metabolites of polyamine metabolism (including elevated N-acetylputrescine levels) is suggestive of BABS.
- Diagnosis by molecular genetic testing for heterozygous pathogenic de novo variant of the ODC1 gene.

Related signaling pathways:

L-methionine salvage cycle III
Regulation of activated PAH-2p34 by proteasome-mediated degradation
Protein homodimerization activity
Ornithine decarboxylase activity

Paralog: AZIN2

1.305. CAPRIN1, Cell Cycle Associated Protein 1

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

Moyamoya angiopathy

Related Paths:

RNA binding
RNA binding

Paralog: CAPRIN2

CAPRIN1 can regulate the transport and translation of mRNAs of proteins involved in synaptic plasticity in neurons and cell proliferation and migration in various cell types. CAPRIN1 binds directly and selectively to MYC and CCND2 RNAs. CAPRIN1 binds directly to several mRNAs associated with RNA granules in neuronal cells, including BDNF, CAMK2A, CREB1, MAP2, NTRK2 mRNAs, and GRIN1 and KPNB1 mRNAs, but not to rRNAs.³

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 critical for synaptic plasticity, as well as mRNAs encoding proteins important for cell proliferation and migration in various cell types.
CAPRIN1 loss-of-function variants were associated with the following symptoms:⁴

Speech Impairment/Language Delay (100%)
mental disability (83%)
ADHD (82 %)
ASA (67 %)
Breathing problems (50%)
Anomalies of the limbs and skeleton (50%)
Developmental delays (42 %)
Feeding problems (33 %)
Seizures (33%)
Eye problems (33 %)

1.306. ANKRD11, Ankyrin Repeat Domain Containing 11

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

The protein ANKRD11 contains an ankryin 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.⁵
ANKRD11 is associated with:

rare genetic intellectual disabilities
KBG Syndrome
- KBG is a rare syndrome. Genetic variants in ankyrin repeat domain 11 (ANKRD11) and deletions in 16q24.3 can cause KBG syndrome. In a group of 25 KBG sufferers, 24% were diagnosed with ADHD.⁶
  KBG goes hand in hand with⁷
  - Macrodontia
  - pronounced craniofacial features
  - Dwarfism
  - Skeletal anomalies
  - global developmental delay
  - Seizures
  - mental disability
  - Hearing loss and/or middle ear infection
  - Visual disturbances
  - Cryptorchidism
  - Cardiopathy
  - Feeding problems

1.306. 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

ANKRD17 is associated with:

ANKRD17-related neurodevelopmental syndrome⁸
- Developmental delays, especially in speech
- variable mental disability characterized
- Other features:
  - ASS
  - ADHD
  - ophthalmological anomalies (strabismus, refractive errors)
  - Growth disorders
  - Nutritional difficulties
  - recurrent infections
  - Gait and/or balance disorders
  - Epilepsy
- Characteristic craniofacial features:
  - triangular face shape
  - high front hairline
  - deep-set and/or almond-shaped eyes with periorbital fullness
  - deep-set ears
  - thick nostrils
  - flared nostrils
  - full cheeks
  - thin vermilion leather on the upper lip
  - rarer
    - Cleft palate with Pierre Robin sequence
    - Renal agenesis
    - Scoliosis.
Chopra-Amiel-Gordon syndrome
non-specific syndromal intellectual disabilities
KBG Syndrome
- KBG is a rare syndrome. Genetic variants in ankyrin repeat domain 17 (ANKRD17), ANKDR 11 and deletions in 16q24.3 can cause KBG syndrome.
- For more on KBG syndrome, see ANKRD11, Ankyrin Repeat Domain Containing 11

1.278. 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) 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 multiple domains, including a CXXC zinc finger, three PHD zinc fingers, two FY-rich domains, and a SET (Suppressor of Variegation, Enhancer of Zeste, and Trithorax) domain. The SET domain is a conserved C-terminal domain characteristic of mixed-lineage leukemia (MLL) family proteins. 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 methyl group transfer from S-adenosyl-L-methionine to the epsilon-amino group of “Lys-4” of histone H3 (H3K4) via a non-processive mechanism. As part of the machinery for chromatin remodeling, it predominantly 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 accumulation 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), the global transcriptional silencing that precedes resumption of meiosis, oocyte survival, and normal activation of the zygotic genome.⁹
KMT2B is associated with

intellectual development disorder, autosomal dominant 68
Tumor (possibly)
Dystonia 28, onset in childhood
KMT2B-Related Dystonia is associated with ADHD Symptoms.¹⁰
- Gene variants that can trigger the so-called “KMT2B-Related Dystonia” are:
  - heterozygous pathogenic variant in KMT2B or
  - has heterozygous interstitial deletion of 19q13.12 that includes a KMTB2 whole-gene deletion
- KMT2B-Related Dystonia is a very rare disorder. To date, 39 affected individuals are known.
- Onset of dystonia usually within the first decade of life, but may occur in the second decade or later
- First appearance:
  - Mostly lower limb dystonia, manifested as:
    - Toe Walk
    - abnormal gait
    - Balance disorders
  - Rarer:
    - Dystonia of the upper limbs
    - cervical or truncal dystonia
- With increasing age:
  - marked cervical, laryngeal, and/or cranial dystonia, manifested as
    - Retrocollis
    - Wryneck
    - Dysarthria/anarthria
    - Dysphonia
    - Difficulty swallowing and chewing
- Within two to 11 years after onset: development 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.¹⁰

1.321. H1-4

Other names: H1.4 linker histones, 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. Histones H1 are necessary for the condensation of nucleosome chains into higher structured fibers. It further acts as a regulator of individual gene transcription through chromatin remodeling, nucleosome spacing, and DNA methylation.¹¹

H1-4 is associated with

Hist1h1e syndrome (Rahman syndrome)¹²
- Mental retardation (mild to severe) (100%)
- Abnormal brain MRI (92%)
  - especially anomalies of the corpus callosus
- Cryptorchidism (75%)
- Hypotension (67%)
- Behavioral problems (59%)
  - Fear, phobias
  - compulsive behavior
  - ADHD
  - Aggression
  - auditory hypersensitivity
  - ASA symptoms
- Skeletal features (54 %)
- Abnormal dentition (51%)
  - Crumbling teeth
  - missing teeth
  - multiple caries
- Congenital cardiac anomalies / Abnormal echocardiogram (40%)
  - Atrial septal defect most common
- Hypothyroidism (29%)
- delayed motor development