Metabolic Ataxias

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METABOLIC ATAXIAS

Abetalipoproteinemia: MTP; 4q22
AMACR: 5p13
Biotinidase Deficiency: 3q25
Carnitine acetyltransferase: 9q34
Cerebrotendinous Xanthomatosis: CYP27A1; 2q33
Gamma-Glutamyl Cysteine Synthetase: 6p12
Glutaminase: 2q32
Hartnup: SLC6A19; 5p15
Hydroxyglutaric aciduria
D-2 & L-2
L-2
Hyperammonemic: Urea cycle
Hypobetalipoproteinemia: APOB; 2p24, 3p22
Maple Syrup Urine Disease: BCKDHB; 19q13
3-Methylglutaconic aciduria: DNAJC19; 3q26
Niemann-Pick, Type C: NPC1; 18q11
Recessive ataxias
Refsum Disease: PHYH; 10pter
Wilson's DiseaseATP7B; 13q14

General features

Usually Autosomal Recessive
Multisystem Involvement
Dietary treatments often effective

Also see
Recessive ataxias

Hartnup

● SLC6A19

; Chromosome 5p15.33; Recessive

SLC6A19 protein
- Na+-dependent amino acid transporter
- Transports neutral amino acids
Biochemistry
- Abnormal neutral α-amino acid transport
  - Renal & Intestinal
Clinical Features
- Rash: Photosensitive
- Ataxia: Intermittent
- Emotional Instability
- Seizures
Treatment
- Nicotinamide: 25 mg/day

Maple Syrup Urine Disease (Intermittent Form)

● Branched chain keto acid dehydrogenase E1, beta polypeptide (BCKDHB)

; Chromosome 6q14.1; Recessive

Genetics
- Mutations: Missense & Nonsense
- Ashkenazi Jewish: Arg183Pro
BCKDHB Protein
- Location: Mitochondrial, matrix
- Branched-chain alpha-keto dehydrogenase complex: Components
  - Heterotetrameric (α2 , β2) branched-chain alpha-keto acid decarboxylase (E1)
  - Homo-24-meric dihydrolipoyl transacylase (E2)
  - Homodimeric dihydrolipoamide dehydrogenase (E3)
  - Regulatory enzymes: Kinase; Phosphorylase
- Catalyzes overall conversion of alpha-keto acids to acyl-CoA and CO₂
- Catabolism of branched-chain amino acids: Isoleucine, Lucine, Valine
- Mutations: Block in decarboxylation of BCAA, leucine, isoleucine & valine
Clinical Features
- Onset age: During 2nd year
- Intermittent events
  - Ataxia, Mitochondrial
  - Drowsiness
  - Seizures
- Attacks after infection, surgery, high protein
- Patients without therapy
  - Mental retardation
  - Extrapyramidal: Dystonia; Athetosis; Dysarthria
  - Weakness: Tetraplegia
  - Ophthalmoplegia
  - Hearing loss
  - Neuropathy: Subclinical (30%)
    - Sural SNAPs: Mildly slow
- Acute axonal neuropathy²
  - Genetics: ? Specific mutation
  - Epidemiology
    - 25 year-old female: Treated for MSUD
  - Onset
    - Age: Young adult
    - Course: Over days
  - Clinical
    - Weakness
      - Legs > Arms
      - Symmetric
      - Severe
    - Tendon reflexes: Reduced or Absent
    - Sensory
      - Loss: Pan-modal
      - Pain: Later in course
    - Cranial nerves: Normal
    - Course: Slow moderate improvement
  - Laboratory
    - NCV: Axonal loss; Small SNAPs & CMAPS; Distal > Proximal
    - Nerve biopsy: Axonal loss; Endoneurial edema
    - Lactic acid: Normal then High later in course
    - Branched chain amino acids (BCAA): High; Exacerbation
Lab
- High serum branched chain amino acids (BCAA)
- Brain MRI
  - White matter pathology: T2 hyperintensity
  - Involvement of thalami & globus pallidus
Treatment
- Protein restriction
- Thiamine-responsive subgroup
  - Acute: 1 g/day
  - Chronic: 100 mg/day
- Dialysis (Acute episodes)
Also see: DLD mutations, Leigh syndrome & MSU disease, type III

Hyperammonemic & Urea cycle Disturbances (Early or Late Onset)

General biochemistry: Partial enzyme deficiencies
Specific Urea Cycle Enzymes
- Argininosuccinic acidemia (ASA) (ASL)
- SLC25A15 (ORNT1) (Mitochondrial): HHH syndrome
- Carbamoyl-phosphate Synthetase Deficiency (Mitochondrial)
  ● CPS1 ; Chromosome 2q34; Recessive
- Citrullinemia
  ● Arginosuccinate Synthetase (ASS1) ; Chromosome 9q34.11; Recessive
- Ornithine Transcarbamylase Deficiency, Hyperammonemia
  ● Ornithine carbamoyltransferase (OTC) ; Chromosome Xp21.1; X-linked recessive
Clinical
- Intermittent episodes
  - Ataxia
  - Consciousness: Confusion, Lethargy, Vomiting
  - After protein loads
- Early onset forms: With severe deficiencies
  - Seizures
  - Coma
  - Mental retardation
- OTC deficiency
  - Sodium valproate sensitivity
  - Heterozygous females
    - May have episodes: With X-inactivation in liver
    - Mutations: Neonatal onset type
- ASL disorders ⁷
  ● Argininosuccinate lyase (ASL) ; Chromosome 7q11.21; Recessive
  - 2nd most common urea cycle defect
  - Biochemistry
    - ASL
      - Cleaves argininosuccinate into arginine & fumarate
        
        Part of NO-citrulline cycle
      - Liver-based urea cycle: Detoxifies ammonia produced by amino acid catabolism
    - Disease: NO deficiency, Systemic
  - Outcomes
    - Developmental delay (90%): More common than in other urea cycle defects
    - Epilepsy (45%)
    - Ataxia (20%)
    - Myopathy-like symptoms (10%)
      - Global hypotonia with hypomimic facial expression
      - Recurrent episodes of general weakness: Persist several days; Spontaneous recovery
    - GI: Liver; Diarrhea
    - Neuroimaging (55%)
      - Focal lesions
      - Diffuse atrophy
      - Creatine: Reduced
      - Guanidinoacetate: Increased
    - Hyperammonemia
      - Frequency: 50% to 100%; More common with early onset
      - Not severe or prolonged
- Treatment
  - Chronic
    - Low protein diet
    - Arginine
  - Acute
    - Na benzoate
    - Na phencyclate
    - Arginine
    - Nitrogen-free i.v. alimentation

Biotinidase Deficiency (Neurocutaneous syndrome)

● Biotinidase (BTD)

; Chromosome 3q25; Recessive
● Holocarboxylase synthetase (HLCS)

Nosology: Multiple carboxylase deficiency
Biotin: Coenzyme for 4 carboxylases
- Pyruvate carboxylase (PCC)
- Propionyl-CoA carboxylase (PCCA)
- α-methylcrotonyl-CoA carboxylase (MCCC1)
- Acetyl-CoA carboxylase (ACACA)
Genetics
- Allelic BTD disorder: Later onset with polyneuropathy
BTD protein
- Holocarboxylase: Covalently binding biotin to apocarboxylases
- Catalyzes hydrolysis of biocytin to biotin & lysine
- Regenerates free biotin
- See: Biotin deficiency
Clinical: Early onset
- Onset: Seizures by 3 months in 50%
- CNS: Spastic ataxia
  - Ataxia
  - Eye
    - Optic Atrophy: Vision loss
    - Conjunctivitis
  - Hearing Loss
  - Developmental Delay
  - Hypotonia
  - Myelopathy
    - Quadriplegia
    - Spasticity
    - Recurrent exacerbations
- Systemic features
  - Skin: Alopecia; Rash (Dermatitis)
  - GI: Hepato-Splenomegaly; Feeding difficulties
  - Respiratory: Tachypnea; Apnea
  - Eye: conjunctivitis
- Treatment
  - Biotin: 10 - 20 mg/day
Laboratory
- Metabolic ketoacidosis
- Organic aciduria
- Hyperammonemia
- Brain MRI: Cerebral & cerebellar atrophy
BTD deficiency variant: Later onset ⁹
- Genetics
  - Mutations: Missense; In-frame deletion
  - Inheritance: Recessive
- Clinical
  - Onset age: 4 years to Adult
  - Optic neuropathy
  - Peripheral neuropathy
    - Numbness
    - Pruritis
    - Pain
    - Legs > Arms
    - Asymmetry: Mild
    - Strength: Normal
    - Tendon reflexes: Normal
    - Course: Slow progression
  - Myelopathy
  - Treatment: Biotin 10 mg/day
- Laboratory
  - Serum biotinidase activity: Markedly reduced
  - NCV: Axons loss; Velocities slowed

L-2 Hydroxyglutaric Aciduria (L2HGA) ¹⁰

● L-2-Hydroxyglutarate dehydrogenase (L2HGDH)

; Chromosome 14q22.1; Recessive

Nosology: Cerebral organic aciduria
Epidemiology: > 60 patients
Genetics
- Mutations: Missens, Nonsense, Splice, Deletion
- Allelic disorders
  - Early onset: 3 months to 6 years
  - Later onset: 6 years to adult
- Other Cerebral organic aciduria
  - Glutaric aciduria type I (GA-I)
L2HGDH protein
- Mitochondrial inner membrane
- Converts L-2-hydroxyglutaricacid (L2HG) to α 2-ketoglutarate
  - Cofactor flavin adenine dinucleotide sodium (FAD)
Clinical: Early onset
- Onset age: Infancy & Early childhood
- Mental Retardation
- Ataxia
- Macrocephaly
- Seizures
- Movement disorders
- Behavior diorders
- ? Increased risk of brain neoplasm
- Course: Slow progression
- Treatment: Riboflavin; Levocarnitine
Laboratory
- CNS imaging: Leukodystrophy, Subcortical with Periventricular sparing
- L-2-hydroxyglutaric (2OHglu; L2HG) acid in urine & CSF
Animal disease: Staffordshire bull terriers
L2HGDH Variant syndrome: Adult onset ⁴
- Mutation: c.959delA
- Clinical
  - Onset: 3rd decade
  - Movement disorder
  - Tremor: Intention
  - Saccades: Slow
  - Progression: Years
  - Treatment: Low lysine diet (60 mg/kg/day)
- Laboratory
  - MRI: White matter T2 hyperintensity
  - Urine L2HG: High

D-2 & L-2 Hydroxyglutaric aciduria (D,L-2-HGA; D2L2AD) ⁵

● Solute carrier family 25 (Mitochondrial carrier, citrate transporter), Member 1 (SLC25A1)

; Chromosome 22q11.21; Recessive

Epidemiology: 13 patients
Genetics
- Mutations: Missense, Splice or Stop; Arg282His, Gly130Asp, P45L, E144Q
- Allelic with: Myasthenic syndrome (CMS23)
SLC25A1 protein: Mitochondrial
- Citrate carrier: Roles in fatty acid & sterol synthesis, gluconeogenesis & glycolysis
- Mitochondrial inner membrane
- Citrate�Malate shuttle
  - Catalyses efflux of citrate/isocitrate from mitochondrial matrix
  - Electroneutral counter-exchange for cytosolic malate
- Required for NMJ formation
- Mutated SLC25A1 protein activity: 0% to 25% of normal
Clinical
- Onset
  - Neonatal
  - Hypotonia
- Epileptic encephalopathy: Severe
- Microcephaly
- Deafness, Sensorineural
- Weakness: Limbs; Fatigable
- Course: No developmental progress, Early death
Laboratory
- Serum & Urine: High D-2- & L-2- Hydroxyglutarate (HG)
  - High D-2 HG also found with neoplasms: Glioma, Thyroid carcinoma, Myeloid leukemia
  - Lactic acid: Normal
- CNS
  - Corpus callosum: Agenesis
  - Optic nerve: Hypoplasia

SLC25A1 variant: Myasthenic syndrome 23 (CMS23) ⁶
- Epidemiology: 8 families, 12 patients
- Genetics
  - Mutations: Asp69Tyr; Arg247Gln (Homozygous)
  - Inheritance: Recessive
- Mutated SLC25A1 protein activity: 40% of normal
- Clinical
  - Onset age: < 2 years
  - Weakness
    - Early: Hypotonia
    - Limbs: Intermittent
    - Ptosis
    - Bulbar: Dysarthria; Fatigable speech
    - Neck
    - Face
    - General strength: Diffusely reduced or Normal
    - Course: Stable
  - Face: Elongated
  - Muscle size: Calf hypertrophy
  - Tendon reflexes: Reduced
  - CNS: Learning difficulties, mild
  - Skeletal: Foot deformities
  - Treatment: 3,4-Diaminopyridine; ? Pyridostigmine
- Laboratory
  - NMJs
    - Repetitive nerve stimulation: Normal
    - SFEMG: Jitter, marked & Blocking
  - Muscle biopsy: Normal or Large mitochondria

Wilson's Disease

● ATPase, Cu⁺⁺ transporting, β polypeptide (ATP7B)

; Chromosome 13q14.3; Recessive

ATPase proteins
Clinical
- CNS
  - Ataxia: Dysarthria; Tremor
  - Extrapyramidal: Athetosis; Dystonia
  - Dementia
- Systemic features
  - Liver Disease
  - Hemolytic Anemia
  - Myopathy ¹¹
- Treatment: Penicillamine

A-β-lipoproteinemia (ABL)

● Microsomal Triglyceride Transfer Protein, large polypeptide (MTTP; MTP)

; Chromosome 4q23

Genetics
- Mutations: > 35 described
- Ashkenazi Jews: Gly865X
MTTP protein
- Chaperone: Facilitates transfer of cholesterol ester & triglyceride onto apolipoprotein B
- Catalyzes transport of triglyceride, cholesteryl ester & phospholipid between phospholipid surfaces
- Location: Lumen of microsomes in liver & intestinal mucosa
- Pathophysiology: Signs due to vitamin E deficiency
Clinical features
- Onset age: Teen & Early Adult
- CNS
  - Ataxia
  - Developmental delay
- Polyneuropathy: Large fiber sensory loss
  - Tendon reflexes: Absent
  - Joint position & Vibration sense: Reduced
  - Gait disorder
  - Strength: Normal
- Systemic features
  - Acanthocytosis
  - Celiac-like Syndrome: Steatorrhea; Fat malabsorption
  - Hepatomegaly
  - Eyes
    - Retinal Degeneration: Pigmentary; Visual loss
    - Optic atrophy
    - External ophthalmoplegia: Some patients
    - Nystagmus
  - Other systemic
    - Cardiomyopathy
    - ? Myopathy
- Treatment
  - High doses of vitamin E: 2,400 to 12,000 IU/day in adults
  - Vitamin A: 100 to 400 IU/kg/day; If an elevated prothrombin time suggests K deficiency
  - Dietary restriction of long-chain fatty acids
Laboratory
- Very low circulating: β-lipoproteins; VLDLs; LDLs; Chylomicrons
- Acanthocytes
- Nerve pathology
  - Myelinated axons: Normal total number; Reduced large size
  - Regenerating axon clusters
- Brain MRI: Atrophy of Cerebellum & Spinal cord

From S Bhimji

Acanthocytes

Hypobetalipoproteinemia

● Apolipoprotein B

; Chromosome 2p24-p23; Dominant

Adult-onset Ataxia in some patients

● Chromosome 3p22-p21.1

; Dominant

Treatment: Vitamin E

Refsum Disease

● Phytanic Acid Oxidase

Demyelinating Polyneuropathy
Ataxia
Eye: Pigmentary Retinal degeneration
Skin: Ichthyosis
Skeletal: 4th metacarpal shortening
Deafness
Cardiac failure
Treatment
- Dietary: Phytanic Acid Restriction

Cerebrotendinous Xanthomatosis (CTX)

● Cytochrome 450, subfamily XXVII (Sterol 27-hydrolase) (CYP27A1)

; Chromosome 2q35; Recessive

Epidemiology
- Onset: Post-pubertal Ataxia
- High incidence: Moroccan Jews
Neuropathy (60%) ¹
- Clinical
  - Sensory loss: Distal; Symmetric
  - Weakness: Distal legs
  - Symmetric
  - Tendon reflexes: Reduced
- Nerve conduction testing: Axonal loss
- Nerve Pathology ³
  - Axon loss: Reduced numbers of Large myelinated axons
  - Demyelination: Some patients; Thin myelin; Small onion bulbs
CNS
- Cerebellar signs (60%)
- Upper motor neuron disorders (90%)
  - Pseudobulbar Dysfunction
  - Paraparesis: Progressive
- Myoclonus
- Dementia
Systemic
- Premature atherosclerosis
- Xanthelasma: Tendons thickened
- Cataracts: Premature, Bilateral
Laboratory
- Cholestanol: Increased in serum & tissues
- Bile alcohol in urine: Increased
- MRI: Cerebellar atrophy
Treatment: Chenodeoxycholic Acid

Gamma-Glutamyl Cysteine Synthetase

● Glutamate-cysteine ligase, catalytic subunit (GCLC)

; Chromosome 6p12

Late-onset Ataxia in 1 family
Hemolytic Anemia
Treatment: ?

Niemann-Pick, Type C (Subacute juvenile form)

● NPC Intracellular cholesterol transporter 1(NPC1)

; Chromosome 18q11-q12; Recessive
● NPC Intracellular cholesterol transporter 2 (NPC2; HE1)

; Chromosome 14q24.3; Recessive

Niemann-Pick: General
- Lysosomal storage disorders
- Classes
  - Types A & B: Sphingomyelinase deficiency; Intracellular sphingomyelin accumulation
  - Types C & D: Accumulation of free cholesterol in lysosomal & late endosomal compartments
Niemann-Pick, Type C
- Frequency: 1 in 100,000 live births
- Types C1 & D: NPC1 mutations
- Type C2: NPC2 (HE1) mutations
Clinical features
- Onset age
  - Usual: 1 to 5 years
  - Range: Neonate to 5th decade
- Cortical: Seizures; Dementia; Psychomotor regression
- Other CNS: More in later onset disease
  - Cerebellar: Ataxia; Dysarthria; Gait disorder; Tremor
  - Extrapyramidal: Athetosis; Dystonia
  - Cataplexy
  - Gaze paresis: Especially down; Also up; Supranuclear; In severe forms
- Hypotonia
- Neuropathy: Hypo-or Demyelination
  - NCV: Mild slowing of velocities; Legs 28 to 33 M/s
  - Distal latency: Prolonged
  - F-waves: Prolonged
- Course: Death 5 to 20 years in childhood onset patients
- Systemic
  - Hepatosplenomegaly: Mild to Severe
- Treatment: ?
Laboratory
- Bone marrow: Foam cells; Sea-blue histiocytes
- Plasma chitotriosidase activity: High
- Skin fibroblasts
  - Intracellular accumulation of cholesterol (Filipin fluoroscence)
  - Low esterification levels
- Peripheral nerve
  - Myelin sheaths: Thin
  - Animal models: Myelin debris & vacuoles in Schwann cells

Carnitine acetyltransferase deficiency

● Carnitine acetyltransferase (CRAT)

; Chromosome 9q34.1; Recessive

Epidemiology: 3 patients described
Genetics
- No gene mutations described
- Possible allelic disorder: NBIA 8
Protein: Fatty acid metabolism
- Catalyzes reversible transfer of acyl groups from acyl-CoA thioester to carnitine
- Control of acyl-CoA/CoA ratio in mitochondria, peroxisomes, and endoplasmic reticulum
- High levels in skeletal muscle
Clinical
- Onset age: Childhood or Infancy
- Ataxia: Intermittent
- Oculomotor palsy
- Hypotonia
- Cortical: Altered consciousness
- Progression: Fatal
Laboratory
- Carnitine acetyltransferase deficiency in brain & systemic
- Muscle: mtDNA deletions, especially ND4-ND4L region
- Cerebellar pathology: Purkinje cell loss
Treatment: ?

3-Methylglutaconic aciduria, type I (MGCA1)

● AU-specific RNA-binding protein (AUH; 3-Methylglutaconyl-CoA hydratase)

; Chromosome 9q22.31; Recessive

Genetics
- Mutations: Stop, Splice or Missense
- Variable penetrance
AUH protein
- RNA-binding protein: AU-binding
- Hydratase
Clinical: Variable phenotype
- Onset age: Infancy to Adult
- Ataxia
- Spasticity
- Extrapyramidal: Dystonia; Athetosis
- Optic atrophy
- Dementia & Psychomotor retardation: Some patients
Laboratory
- Brain MRI: White matter lesions; Cerebral & Basal ganglia atrophy
- 3-Methylglutaconic aciduria
- Metabolic acidosis

Glutaminase deficiency ⁸

● Glutaminase (GLS)

; Chromosome 2q32.2; Recessive

Epidemiology: 3 patients
Genetics
- Inheritance: Recessive
- Mutations: GCA repeat expanison in 5' untranslated region, p.Pro313Leu, c.923dupA
- Allelic disorders
  - Infantile cataract, skin abnormalities, glutamate excess, and impaired intellectual development (CASGID) : Dominant
  - Epileptic encephalopathy, early infantile, 71 : Recessive
GLS protein
- L-Glutamate → L-Glutamate
Clinical
- Onset age: 1 to 3 years
- Ataxia: Gait disorder; Dysarthria; Progressive
- Motor & Speech delay
- Hypotonia
- Seizure: 1 patient
Laboratory
- Glutamine: High
- Brain: Cerebellar atrophy in 1 patient

Also see: Recessive Ataxias

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References
1. Neuromuscular Disorders 2000;10:407-414
2. Muscle Nerve 2001;24:284-287
3. Neuropathology 2007;27:62-66
4. Neurology 2102;78 On line Mar
5. American J Human Genet 2013; Online April, J Med Genet 2013;50:240-245
6. J Neuromuscular Diseases 2014;1:75�90.
7. J Inherit Metab Dis 2017 Mar 1
8. N Engl J Med 2019;380:1433-1441
9. Mol Genet Metab Rep 2020 Dec 15
10. Mol Genet Metab Rep 2023;36:100979
11. Cureus 2025;17:e99405

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