Metabolic Ataxias

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METABOLIC ATAXIAS

Abetalipoproteinemia
Biotinidase Deficiency
Carnitine acetyltransferase
Cerebrotendinous Xanthomatosis
Gamma-Glutamyl Cysteine Synthetase
Hartnup
Hyperammonemic
Hypobetalipoproteinemia
L-2 Hydroxyglutaric acidemia
Maple Syrup Urine Disease
Niemann-Pick, Type C
Recessive ataxias
Refsum Disease
Wilson's Disease

General features

Usually Autosomal Recessive
Multisystem Involvement
Dietary treatments often effective

Hartnup

l 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
Treatment
- Nicotinamide: 25 mg/day

Maple Syrup Urine Disease (Intermittent Form)

l Branched chain keto acid dehydrogenase E1, alpha polypeptide

; Chromosome 19q13.2

Genetics
- Mutations: Missense & Nonsense
- Ashkenazi Jewish: Arg183Pro
BCKDHB Protein
- Location: Mitochondrial
- Branched-chain alpha-keto dehydrogenase complex
- Catalyzes overall conversion of alpha-keto acids to acyl-CoA and CO₂
- Mutations: Block in decarboxylation of BCAA, leucine, isoleucine & valine
Clinical Features
- Intermittent events: Ataxia, Drowsiness, Seizures
- Onset during 2nd year
- 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 Disturbances (Late Onset)

Intermittent ataxia after protein loads
Partial enzyme deficiencies
Early onset forms with severe deficiencies
- Seizures,
- Coma
- Mental retardation
Specific Urea Cycle Enzymes:
- Argininosuccinic acidemia
  l Argininosuccinate lyase ; Chromosome 7q21.3-q22
- Carbamoyl-phosphate Synthetase I
  (Mitochondrial)
  l Chromosome 2q33-q36
- Citrullinemia
  l Arginosuccinate Synthetase; Chromosome 9q34
- Ornithine Carbamoyltransferase
  l Chromosome Xp21.1
Treatment
- Chronic
  - Low protein diet
  - Arginine
- Acute
  - Na benzoate
  - Na phencyclate
  - Arginine
  - Nitrogen-free i.v. alimentation

Biotinidase Deficiency

l Biotinidase

; Chromosome 3q25; Deletion
l Late onset multiple carboxylase deficiency

Onset: Seizures @ 3 months in 50%
CNS: Ataxia; Optic Atrophy; Hearing Loss; Developmental Delay
Systemic features: Alopecia; Skin Rash
Treatment
- Biotin: 10 - 20 mg/day

L-2 Hydroxyglutaric acidemia

Mental Retardation
Ataxia
Macrocephaly
CNS imaging: Leukodystrophy
Treatment: ?

Wilson's Disease

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

; Chromosome 13q14.3-q21.1; Recessive

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

A-β-lipoproteinemia

l Microsomal Triglyceride Transfer Protein, large polypeptide (MTP)

; Chromosome 4q22-q24

Pathophysiology: Signs due to vitamin E deficiency
Onset: Teen & Early Adult
Clinical features
- Ataxia
- Polyneuropathy: Large fiber sensory loss
- Systemic features
  - Acanthocytosis
  - Celiac-like Syndrome: Steatorrhea; Fat malabsorption
  - Retinal Degeneration: Pigmentary
Laboratory
- Very low circulating: β-lipoproteins; VLDLs; LDLs; Chylomicrons
- Nerve pathology
  - Myelinated axons: Normal total number; Reduced large size
  - Regenerating clusters
Treatment
- High doses of vitamins E, ? + A & K

Hypobetalipoproteinemia

l Apolipoprotein B

; Chromosome 2p24-p23; Dominant

Adult-onset Ataxia in some patients

l Chromosome 3p22-p21.1

; Dominant

Treatment: Vitamin E

Refsum Disease

l 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

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

; Chromosome 2q33-qter; 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 Pathology³
  - 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

l Glutamate-cysteine ligase, catalytic subunit (GCLC)

; Chromosome 6p12

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

Niemann-Pick, Type C (Subacute juvenile form)

l NPC1

; Chromosome 18q11-q12; Recessive
l NPC2 (HE1)

; Chromosome 14q24.3; Recessive

Onset usually 1 to 5 years, but also in adult
Clinical features
- Ataxia
- Athetosis; Seizures; Dementia
- Neuropathy: Hypomyelination
- Gaze paresis in severe forms
Death 5 to 20 years in childhood onset patients
Treatment: ?

Carnitine acetyltransferase deficiency

l Carnitine acetyltransferase

; Chromosome 9q34.1; Recessive

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: Childhood or infancy
- Ataxia: Intermittent
- Oculomotor palsy
- Hypotonia
- Cortical: Altered consciousness
- Progression: Fatal
Laboratory
- Carnitine acetyltransferase deficiency in brain & systemic
Treatment: ?

Also see: Recessive Ataxias

Return to Ataxia Syndromes
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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

6/23/2008