Differential Diagnosis in Neurology

Topic 13. Cerebellar Disease

13.2. Autosomal Recessive Ataxias

The Autosomal Recessive Ataxias

  • General considerations:
    • Most are childhood onset
    • May have adult onset
    • Consaniquinity is higher than in the general population, but is not required
    • The parents are asymptomatic
    • In small families only one child may be affected

Friedreich's Ataxia (classic phenotype)

  • General considerations:
    • Most common recessively inherited ataxia; most patients have a GAA repeat expansion of the first intron of frataxin gene
      • Frataxin is a nuclear encoded mitochondrial protein
    • Prevalence of 2 per 100,000 people
      • Long normal alleles (25–40 repeats) occur in Caucasian patients
      • Chromosome 9q13; FRDA gene
      • Associated medical abnormalities:
        • Hypertrophic cardiomyopathy (50%)
        • Repolarization defects on EKG
        • Diabetes mellitus 10%
      • 95% of patients have homozygous GAA expansion in both alleles
  • Clinical features:
    • Onset of less than 25 years of age
    • Mean age of onset is 11–12 years
    • Presentation of progressive gait ataxia
    • Rare presentations:
      • Cardiac dysfunction
      • Scoliosis
    • Loss of position and vibration sensibility of the lower extremities occur early
    • Dysarthria; pes cavus
    • Pes cavus
    • Bilateral Babinski signs
    • Square wave jerks noted with eye movement recording
    • Inability to walk occurs between 10–15 years of illness
    • Loss of muscle strength (late)
    • Flexor spasms
    • Dysphagia
    • Optic atrophy and VIIIth nerve deficits occur late
  • Electrodiagnostic evaluation (EMG/NCV):
    • Early decrease of SNAP (sensory nerve action potential)
    • Central conduction defects occur late
  • MRI evaluation:
    • Atrophy of the upper cervical cord greater than cerebellar atrophy

Atypical Phenotypes of Friedreich's Ataxia

Late Onset

  • General considerations:
    • Onset later than age 25 years occurs in 7–17% of patients
    • Classic onset with preservation of ankle jerks
      • 5–13% of patients
      • Small number of patients have late onset with preserved reflexes
    • Larger repeat size:
      • Correlated with hypertrophic cardiomyopathy and DM (diabetes mellitus)
    • Somatic musacism may account for variability of presentation

Early Onset

  • General considerations:
    • Two missense mutations located in the amino-terminal half of the frataxin gene
    • Loss of function mutation (D122Y and G130V)
  • Clinical features:
    • Atypical and milder clinical presentation
    • Early onset of spastic gait
    • Slow disease progression
    • No dysarthria
    • Retained or brisk tendon reflexes
    • Minimal cerebellar ataxia
    • Optic disc pallor:
      • Higher in compound heterozygotes than in expansion homozygotes

Intrafamilial Phenotypic Variability in Friedreich Ataxia Associated with a G130V Mutation in the FRDA Gene

  • General considerations:
    • GAA expansion on one allele and a point mutation on the other
  • Clinical features:
    • Slow disease progression
    • Minimal or no ataxia
    • Increased deep tendon reflexes
    • Mild gait spasticity
  • Neuropathology:
    • Loss of myelinated fibers in peripheral nerves
    • Decrease of large dorsal root ganglion cells
    • Demyelination of the dorsal columns
    • Distal degeneration of the corticospinal pathways ("dying back")
    • Degeneration of the spinocerebellar pathways
    • Loss of neurons occurs in Purkinje cells, cranial nerve neurons and dentate nucleus
    • Cerebellum and brainstem are less affected

Ataxia Telangiectasis (A-T)

  • General considerations:
    • Second most common recessive ataxia
    • Frequency of 1:400,000 births in the USA
    • Most frequent in ethnic groups with high consanguinity; seen among all races
    • Lack ATM protein or ATM kinase activity; chromosome 11q22–23
    • Absence or dysfunction of the ATM gene; splicing and missense mutations
    • Ataxia telangiectasias variants:
      • Nijmegan syndrome (NBS) or nibrin/Nbs1 deficiency
        • Mental retardation with microcephaly
        • No ataxia, apraxia or telangiectasias
      • A-T (Fresno)
        • Features of both NBS and A-T
          • Mutations in the A-T M gene
    • Cells from A-T are extremely sensitive to ionizing irradiation or other DNA damaging agents
    • ATM protein is involved in mobilizing the cellular response to DNA double stranded breaks
  • Clinical features:
    • Early onset and progressive
    • Ataxia by age two
    • Wheelchair bound by 12 years of age
    • Oculocutaneous telangiectasia occur several years after onset
    • Oculomotor apraxia
    • Dysarthria
    • Immunodeficient patients with frequent sinopulmonary infection
    • Lymphoid cancer occurs in 1/3 of patients
    • Short stature and mental retardation are common
    • Choreoathetosis may be prominent
  • MRI Evaluation:
    • Decreased volume of the cerebellum by age 10; progression of atrophy in the hemispheres from lateral and superior to inferior
  • Laboratory Evaluation:
    • Elevated albumin to globulin
    • Deficiency of IgA, IgE, and IgG2
    • Low T cell levels with poor response to mitogin
    • Translocations and telomeric fusions; increased ratio of telomeric shortening
    • In vitro radiosensitivity of cells
    • Deficits in the activation of cell cycle check points
    • Decreased ATM protein
    • Deficient phosphorylation of p53, nibrin/Nbs1, Mdm2, Smc1, Mre11

Variability within the classical A-T Phenotype

  • Late development of ataxia (teens)
  • No telangiectasias (usually seen on bulbar conjunctive, but also bridge of the nose, pinna, antecubital fossae, knuckles and behind the knee
  • Cancer phenotype:
    • β lineage lymphocytes
    • T cell lineage in teenagers
    • Non-lymphoid malignancies
  • No mental retardation; some patients with higher than normal IQ
  • Laboratory evaluation:
    • 15% of patients have some ATM protein; some normal ATM (poor function)
  • ATM phosphorylates proteins involved in cell regulation (to various degrees)

A-T Variants

Nijmegen Breakage Syndrome

  • General considerations:
    • Similar cellular phenotype to A-T
    • Radiosensitivity and translocations of chromosome 7 and 14; immunodeficiency and predisposition to cancer
    • AT-V2 gene (Nijmegen; AT-V2 (Berlin gene for these diseases localized to 8q21)
  • Clinical features:
    • Microcephaly
    • Mental retardation
    • No ataxia or telangiectasia

Mutations of the Mre 11 Gene

  • General considerations:
    • Chromosome 11q21
  • Clinical features:
    • Early onset ataxia
    • Radiosensitivity

Aicardi Syndrome (AOA2 Type II; ataxia with oculomotor apraxia)

  • General considerations:
    • ATM levels are normal
    • No radiosensitivity
    • Gene localized to chromosome 9q34 (creatoxin gene)
    • Increased serum alpha-fetoprotein
    • Found in Europe, North Africa and West Indies
    • Frequency of 8% of non-Friedreich's ARCA
  • Clinical features:
    • Later onset of ataxia (11–22 years of age)
    • Sensorim motor neuropathy (92%)
    • Choreic or dystonic movements (44%)
    • Oculomotor apraxia (56%)
      • Increased horizontal saccade latencies
      • Hypometria
  • Laboratory evaluation:
    • Increased alpha-fetoprotein

Mutations of TDP1

  • General considerations:
    • Tyrosyl-DNA phosphodiesterase (TDP1) repairs covalently bound topo isomerase 1-DNA complexes
      • A step in the DNA repair process
  • Clinical features:
    • Spinocerebellar ataxia
    • Axonal neuropathy

Ataxia – Oculomotor Apraxia 1 Gene (AOA 1)

  • General considerations:
    • AR; gene is on chromosome 9p13; codes for aprataxin
    • In vitro cells do not have radioresistant DNA; they do have normal ability to phosphorylate targets of ATM
  • Clinical features:
    • Early onset of ataxia
    • Oculomotor apraxia
  • Laboratory evaluation:
    • Not radiosensitive by CSA; but are sensitive to hydrogen peroxide and agents that cause single strand DNA breaks
    • Normal AFP levels

Ataxia with Vitamin E Deficiency

  • General considerations:
    • Decreased alpha-tocopherol levels
    • Chromosome 8q; point mutation in the gene that encodes the alpha-tocopherol transporter
      • Childhood onset phenotype
        • ccurs with mutations that inactivate the transporter
      • Adult onset phenotype:
        • Some residual transporter activity remains
  • Clinical features:
    • Early onset of progressive ataxia
    • Severe proprioceptive loss
    • Areflexia
    • Retinal disease
    • Head trauma
    • Chorioretinitis
    • Rare cardiomyopathy

Spastic Ataxia of Charlevoix-Saquenay

  • General considerations:
    • Chromosome 13q11; mutated protein SACS
    • Transcribed protein is sacsin
  • Clinical features:
    • Seen amongst French Canadians of the Charlevoix-Saquenay province of Quebec
    • Spasticity
    • Ataxia

Rare AR Cerebellar Ataxias

Hypogonadotrophic hypogonadism (Holmes)

  • Clinical features:
    • Abnormal sexual development
    • Neurologic symptoms develop in the 3rd decade
    • Dysarthria, nystagmus, progressive gait and limb ataxia
    • Mental retardation, dementia, distal weakness, choreoathetosis, retinopathy, dorsal column defects
  • Behr's Syndrome
    • Clinical features:
      • Scoliosis
      • Spasticity
      • Optic atrophy
      • Learning disability
  • Marinesco-Sjögren
    • Clinical features:
      • Learning disability
      • Short stature
      • Myopathy
      • Nail infections
      • Delayed sexual development
  • DIDMOAD (Wolfram's Syndrome)
    • Clinical features:
      • Diabetes insipidus
      • Diabetes mellitus
      • Optic atrophy
      • Deafness
      • Ataxia
      • Short arm of chromosome 4
  • Autosomal recessive cerebellar ataxia syndrome with upward gaze palsy, neuropathy and seizures
    • Clinical features:
      • Early onset ataxia
      • Dysarthria
      • Myoclonic and generalized tonic clonic seizures
      • Upward gaze palsy
      • Extensor plantar reflexes
      • Sensory neuropathy
      • Normal cognition
  • Autosomal recessive late-onset ataxia
  • Recessive ataxia with pigmentary retinopathy
    • Clinical features:
      • Mental retardation
      • Deafness
      • Peripheral neuropathy
      • Pigmentary retinopathy
  • Early onset cerebellar ataxia with mental retardation
  • Childhood onset deafness
    • Ataxia develops in midlife
  • Congenital deafness
    • Ataxia develops in the third decade
  • X-linked spastic ataxic syndromes
  • Early onset cerebellar ataxia:
    • General considerations:
      • Most patients have mutations in the frataxin gene
      • Prognosis is better than for patients with Friedreich's ataxia
    • Clinical features:
      • Onset between 2–20 years of age
      • Biceps, triceps and knee jerks are normal or increased
      • Absent ankle jerks
      • No optic atrophy, dilated cardiomyopathy or scoliosis
    • MRI evaluation:
      • More cerebellar atrophy than Friedreich's ataxia
    • Neuropathology:
      • Some patients have similar pathology to OPCA

Ramsay–Hunt Syndrome

  • General characteristics:
    • AR inheritance
  • Clinical features:
    • Progressive cerebellar ataxia
    • Myoclonus
    • Dementia
    • Seizures

Unverricht–Lundborg (Baltic myoclonus)

  • General characteristics:
    • Chromosome 21 q; gene cystatin B
  • Clinical features:
    • Stimulus sensitive myoclonus
    • Seizures
    • Ataxia and dysarthria
    • Pyramidal tract dysfunction

Differential Diagnosis of Progressive Myoclonic Ataxia

  • Mitochondrial encephalopathy
  • Sialidosis
  • Ramsay-Hunt
  • Ceroid lipofuscinosis
  • Coeliac disease
  • Some patients with cystatin B mutations

Recessive Syndromes with Prominent Ataxia

  • Cerebrotendinous xanthomatosis
  • Partial hypoxanthine guanine phosphoribosyl deficiency
  • Wilson's disease
  • Late onset hexosaminidase deficiency
  • Refsum's disease
  • Adrenomyeloneuropathy
  • Mitochondrial DNA mutations:
    • 8344, 3243, 8993
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