Molecular Genetics.

The disease is genetically heterogeneous. In most pedigrees (known as HMSN IA or CMT1A), there is a duplication of a large region of chromosome 17p11.2-p12, resulting in

"segmental trisomy" of the duplicated region. The duplicated segment includes the gene for

TABLE 27-3-- Hereditary Neuropathies Accompanying Inherited Metabolic Disease

Disease Metabolic Defect Inheritance Clinical Findings Pathologic Findings

Adrenoleukodystrophy ATP-binding cassette, or ABC,

transporter protein, subfamily D,

member 1 (ALD protein, or

ABCD1) gene; Xq28

X-linked; 4% of female

carriers are symptomatic

Mixed motor and sensory neuropathy, adrenal

insufficiency, spastic paraplegia; onset between

10 and 20 years for males with leukodystrophy,

between 20 and 40 years for females with

myeloneuropathy

Segmental demyelination, with onion

bulbs; axonal degeneration

(myelinated and unmyelinated);

electron microscopy; linear inclusions

in Schwann cells

Familial amyloid

polyneuropathies

Transthyretin (TTR) gene (rarely

other genes); 18q11.2-q12.1

Autosomal-dominant Sensory and autonomic dysfunction; age at

onset varies with site of mutation

Amyloid deposits in vessel walls and

connective tissue with axonal

degeneration

Porphyria, acute

intermittent (AIP) or

variegate coproporphyria

Enzymes involved in heme

synthesis (acute intermittent

porphyria—porphobilinogen

deaminase deficiency; 11q24.1-

q24.2)

Autosomal-dominant Acute episodes of neurologic dysfunction,

psychiatric disturbances, abdominal pain,

seizures, proximal weakness, autonomic

dysfunction; attacks may be precipitated by

drugs

Acute and chronic axonal

degeneration; regenerating clusters

Refsum disease Peroxisomal enzyme phytanoyl

CoA a-hydroxylase (PAHX)

gene; 10pter-p11.2

Autosomal-recessive Mixed motor and sensory neuropathy with

palpable nerves; ataxia, night blindness,

retinitis pigmentosa, ichthyosis; age at onset

before 20 years (a genetically distinct infantile

form also exists)

Severe onion bulb formation

peripheral myelin protein 22 (PMP22), but whether the disease is caused by overexpression of PMP22, by gene dosage effect,[28] [29] or by duplication of other adjacent genes is not

clear. A separate genetic locus on chromosome 1 involves myelin protein zero (MPZ) but produces an identical clinical phenotype (HMSN IB).[26] A third set of pedigrees shows linkage

to chromosome 16p, and is associated with mutations in a gene whose product is involved in protein degradation pathways.[30] In addition, some pedigrees are associated with mutations

in the gene for the gap junction protein connexin-32, which is located on the X chromosome.[31]

Morphology.

CMT1 is a demyelinating neuropathy, both by nerve conduction velocity studies and pathologically. Histologic examination shows the consequences of repetitive demyelination and

remyelination, with multiple onion bulbs, more pronounced in distal nerves than in proximal nerves (see Fig. 27-5 ). The axon is often present in the center of the onion bulb, and the

myelin sheath is usually thin or absent. The redundant layers of Schwann cell hyperplasia surrounding individual axons are associated with enlargement of individual peripheral nerves

that may be individually palpable, which has led to the term hypertrophic neuropathy. In the longitudinal plane, individual segments of the axon may show evidence of segmental

demyelination. Autopsy studies of affected individuals have shown degeneration of the posterior columns of the spinal cord.

Clinical Course.

The disorder is usually autosomal-dominant, and although it is slowly progressive, the disability of sensorimotor deficits and associated orthopedic problems such as pes cavus are

usually limited in severity, and a normal life span is typical. The relationship between the molecular events and the observed peripheral nerve pathology is not well understood.

Date: 2016-04-22; view: 798