Wallach's Interpretation of Diagnostic Tests: Pathways to Arriving at a Clinical Diagnosis (445 page)

SPINAL CEREBELLAR ATAXIAS

SPINOCEREBELLAR ATAXIA TYPE 1 (SCA1; OLIVOPONTOCEREBELLAR ATROPHY 1; OPCA1)

MIM #164400

   Definition

The clinical manifestations of autosomal dominant inherited spinocerebellar ataxias are caused by the variable pathologic involvement of the brain stem and spinal cord, that results in cerebellar degeneration. Spinocerebellar ataxia-1 (SCA1) is caused by expansion of a CAG trinucleotide repeat in the ataxin-1 gene (ATXN1; 6p22.3).

Relevant Tests and Diagnostic Value

Polymerase chain reaction (PCR) and fragment analysis by capillary electrophoresis of CAG triplet repeat expansion in the
AATXN1
gene; normal: ≤ 35 CAG trinucleotide repeats.

Suggested Readings

Margolis RL. Dominant spinocerebellar ataxias: a molecular approach to classification, diagnosis, pathogenesis and the future.
Expert Rev Mol Diagn.
2003;3:715–732.

Orr HT, et al. Expansion of an unstable trinucleotide CAG repeat in spinocerebellar ataxia type 1.
Nat Genet.
1993;4:221–226.

van de Warrenburg BP, et al. Age at onset variance analysis in spinocerebellar ataxias: a study in a Dutch-French cohort.
Ann Neurol.
2005;57:505–512.

WILSON DISEASE (HEPATOLENTICULAR DEGENERATION)

MIM #277900

   Definition

Wilson disease is an autosomal recessive disorder caused by mutations in the ATPase, Cu
²⁺
-transporting, beta polypeptide gene (ATP7B) at 13q14 that encodes a polypeptide functioning as a plasma membrane copper transport protein. This disorder is characterized by buildup of intracellular hepatic copper that results in cirrhosis and neurologic abnormalities. There is a wide range in the age of onset of Wilson disease, including early childhood. Diagnosis of Wilson disease is dependent on both clinical and laboratory evidence of abnormal copper metabolism. A deep copper-colored Kayser-Fleischer ring may be present at the periphery of the cornea.

   Relevant Tests and Diagnostic Value

   Low serum ceruloplasmin and/or high urinary copper.

   Mutation detection: Sequence analysis of the entire coding regions; deletion/ duplication analysis; targeted mutation analysis.

   MRI may show increased signal intensities in the basal ganglia.

Suggested Readings

De Bie P, Muller P, Wijmenga C, et al. Molecular pathogenesis of Wilson and Menkes disease: correlation of mutations with molecular defects and disease phenotypes.
J Med Genet.
2007;44:673–688.

Gow PJ, Smallwood RA, Angus PW, et al. Diagnosis of Wilson’s disease: an experience over three decades.
Gut.
2000;46:415–419.

   
NEUROMUSCULAR DISORDERS

AMYOTROPHIC LATERAL SCLEROSIS (ALS; LOU GEHRIG DISEASE)

MIM #105400

   Definition

Diagnosis of ALS is dependent on a thorough medical and neurologic examination, as well as clinical and laboratory diagnostic testing, to rule out treatable diseases that have symptoms similar to ALS. Clinical testing can include electrodiagnostic tests: electromyography (EMG) and nerve conduction velocity (NCV), x-rays, magnetic resonance imaging (MRI), spinal tap, myelogram of the cervical spine, and muscle and/or nerve biopsy. Determination of family history and genetic counseling are important. Ninety percent of ALS patients have no family history (sporadic ALS; SALS), and inheritance patterns can be autosomal dominant, autosomal recessive, or X-linked. The most common inheritance pattern in approximately 10% of patients having familial ALS (FALS) is autosomal dominant. Mutations in the SOD1 (21q22.11), TARDBP (1p36; encodingTDP-43), FUS (16p11.2), C9ORF72 (9p21.2), and UBQLN2 (Xp11.21) genes have been identified in approximately 50% of FALS patients.

   Who Should Be Suspected?