CMT 1A pathology article

[Guest guest]

I found these statements to be of particular interest.

From the Departments of Pediatric Neurology (Dr Al-Muhaizea) and Anatomic

Pathology (Dr Prayson), Cleveland Clinic Foundation, Cleveland, Ohio

In most cases, the duplication is inherited from an affected parent; however,

there is evidence to indicate that the duplication can arise de novo, without

a prior family history.

CMT1 is inherited as an autosomal dominant disorder, with up to 20% of cases

representing new mutations (with no family history). 2 The typical features of

CMT include distal muscle weakness and atrophy, impaired sensation, and

absent or hypoactive deep tendon reflexes. Approximately one third of patients

have

an essential or postural tremor.

Kat

Seattle WA USA

http://www.icewindow.com

[Guest guest]

From Archives of Pathology and Laboratory Medicine: Vol. 127, No. 6, pp.

e273–e274. 2003 June

Pathologic Quiz Case: A Child With Clumsy Gait Mohammad A. Al-Muhaizea,

MD,a and A. Prayson, MDa

From the Departments of Pediatric Neurology (Dr Al-Muhaizea) and

Anatomic Pathology (Dr Prayson), Cleveland Clinic Foundation, Cleveland,

Ohio

A 6½-year-old boy presented to our institution with excessive falling

and poor motor skills. His medical history and family history were

noncontributory. His performance in school was above average. Since the

age of 18 months, when he took his first steps, he was clumsy,

particularly when running and walking, with frequent falls and

difficulty getting up from the floor. No symptoms suggestive of upper

extremity or cranial nerve involvement were elicited. There was no

associated pain, cramps, diurnal change, or fatigability. Physical

examination revealed bilateral lower extremity weakness, slightly more

distal than proximal, with generalized areflexia and a mild decreased

vibratory sense in the lower extremities up to the ankles. Electrolyte

and creatinine kinase levels were normal. An electromyogram revealed a

generalized demyelinative sensory and motor peripheral neuropathy. A

muscle biopsy specimen showed angular, atrophic, esterase-positive

myofibers with grouped atrophy and fiber type grouping, consistent with

chronic active neurogenic atrophy. A sural nerve biopsy specimen showed

a mild loss of myelinated axons and thinly myelinated axons (Figure 1 ).

Repeated demyelination and remyelination in the form of prominent onion

bulb formations were evident both by light microscopy (Figure 1 ) and

ultrastructural examination (Figure 2 ).

Pathologic Diagnosis: Charcot-Marie-Tooth Type 1A

The hereditary disorders of the peripheral nerves constitute a group of

frequently encountered neurologic diseases. Charcot-Marie-Tooth disease

(CMT) is the most common of the hereditary motor and sensory

neuropathies (HMSNs). Estimated frequency is 1 per 2500 according to the

CMT Association.1 The classification of CMT has undergone change

coincident with chromosomal localization and gene identification.1,2

Charcot-Marie-Tooth disease is classified into CMT1 or CMT

(demyelinating), CMT2 (axonal), CMT3 or Dejerine-Sottas disease (DSD),

and CMT4 and X-linked CMTX. CMT1 is inherited as an autosomal dominant

disorder, with up to 20% of cases representing new mutations (with no

family history).2 The typical features of CMT include distal muscle

weakness and atrophy, impaired sensation, and absent or hypoactive deep

tendon reflexes. Approximately one third of patients have an essential

or postural tremor.2 The onset of CMT is typically during the first or

second decade of life, although it may be detected by neurophysiologic

methods in infancy.2–4 The variation in clinical presentation in CMT is

wide, ranging from patients with severe distal atrophy and marked hand

and foot deformities to individuals whose only clinical finding is pes

cavus and minimal or no distal weakness.5 An electromyogram typically

shows moderately to severely reduced nerve conduction velocities.1,2

Nerve pathology is characterized by a reduced number of myelinated nerve

fibers, demyelination, and thinly remyelinated axons. Repeated episodes

of demyelination and remyelination result in the formation of an onion

bulb, a concentrically laminated structure formed by Schwann cell

processes separated by collagen fibers.

Genetic loci for CMT1 map to chromosome 17p11.2–12 (CMT1A), chromosome

1q22–23 (CMT1B), and another unknown autosome (CMTlC).1 Two mechanisms

result in the CMT1A phenotype. In most cases, with duplication at

chromosome 17pll.2–12, an overexpression of the peripheral myelin

protein 22 (PMP-22) gene occurs; in a few cases with a point mutation,

an abnormal PMP-22 protein level appears to give rise to the disease

phenotype CMTIA.2,3,6 In most cases, the duplication is inherited from

an affected parent; however, there is evidence to indicate that the

duplication can arise de novo, without a prior family history.2 A total

of 70% to 80% of patients with a clinical diagnosis of CMT1 demonstrate

the 17p1.2–12 duplication. Molecular testing for the duplication may

provide a useful marker for screening family members suspected of having

the condition.5 Among the other HMSNs, 2 types may show onion bulb

formation. Type III or DSD is a disease of infancy with progressive

motor and sensory loss, pes cavus, and often scoliosis.6,7 It is an

autosomal recessive disorder; however, the disability is worse and on

biopsy specimens there is a significantly lower density of large

myelinated fibers, a greater frequency of onion bulbs, more lamellae per

onion bulb, and a higher ratio of mean axon diameter.6,7 The onion bulb

lamellae contain little cytoplasm and frequently consist of opposed

double-layered basement membranes. Schwann cell nuclei are prominent.8

Myelin debris is sometimes observed in macrophages and Schwann cells.

The HMSN with focally folded myelin sheaths has an onset in the neonatal

period or early childhood, and the mode of inheritance is autosomal

recessive.7,8 The clinical, genetic, and electrophysiologic features

resemble DSD, but the striking morphologic feature differentiating it

from DSD is the presence of aberrant hypermyelination. The biopsy

specimen shows a loss of myelinated fibers, segmental demyelination and

remyelination with onion bulb formation, and numerous focal myelin

thickenings.8 From a pathologic standpoint, the concentric proliferation

of Schwann cells in response to demyelination and subsequent

remyelination results in onion bulbs, which are the hallmark of

hypertrophic neuropathy. This can be seen in small numbers in almost any

chronic demyelinative condition; however, in onion bulb or hypertrophic

neuropathies, they are the predominant histologic finding.6

The differential diagnosis includes degenerative disorders that affect

both the central nervous system (CNS) and peripheral nervous system,

especially metachromatic leukodystrophy, Krabbe disease, and Refsum

disease.7–9 These can be differentiated on the basis of CNS involvement

(eg, cognitive decline, seizures, blindness, radiologic evidence of CNS

involvement) and presence of abnormal storage material in nerve biopsy

specimens (eg, metachromatic leukodystrophy and Refsum disease).8,9 The

differential diagnosis also includes chronic inflammatory demyelinating

polyneuropathies, which have a characteristic relapsing and remitting

course, easily differentiated from CMT by electromyography and the

inflammatory changes on the biopsy specimen.9 In addition, chronic

disorders, such as diabetes that is obvious clinically and ischemia,

would result in focal neuropathy.7,9 Toxic polyneuropathies generally

produce axonal loss; however, arsenic may produce a predominantly

demyelinating picture that resembles a chronic inflammatory

demyelinating polyneuropathy.9 The diagnosis is established by obtaining

levels of arsenic in blood, urine, hair, and nail samples.9

References

1. Ionasescu, VV. Charcot-Marie-Tooth neuropathies: from clinical

description to molecular genetics. Muscle Nerve 1995;18:267–275.

2. Mendell, JR. Charcot-Marie-Tooth neuropathies and related disorders.

Semin Neurol 1998;18:41–47.

3. Warner, LE, CA , and JR. Lupski. Hereditary peripheral

neuropathies: clinical forms, genetics, and molecular mechanisms. Annu

Rev Med 1999;50:263–275.

4. Guzzetta, F, J , M Deodato, A Guzzetta, and G. Ferriere.

Demyelinating hereditary neuropathies in children: a morphometric and

ultrastructural study. Histol Histopathol 1995;10:91–104.

5. Keller, MP, and PF. Chance. Inherited peripheral neuropathy. Semin

Neurol 1999;19:353–359.

6. Schmidt, RE. Demyelinating diseases. In: JS, Parisi JE,

Schochet SS, eds. Principles and Practice of Neuropathology. St Louis,

Mo: Mosby-Year Book Inc; 1993:361–397.

7. , PK, DN Landon, and RHM. King. Diseases of the peripheral

nerves. In: Graham DI, Lantos PL, eds. Greenfield's Neuropathology. 6th

ed. London, England: Arnold Publishing Co; 1997:367–488.

8. Vital, A, and C. Vital. Peripheral neuropathies. In: Duckett S, ed.

Pediatric Neuropathology. Malvern, Pa: & Wilkins; 1995:767–784.

9. Mc, CM. Peripheral neuropathies of childhood. Phys Med Rehab

Clin North Am 2001;12:473–490.

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Corresponding author: A. Prayson, MD, Department of Anatomic

Pathology (L25), Cleveland Clinic Foundation, 9500 Euclid Ave,

Cleveland, OH 44195