congenital hypomyelinating neuropathy · congenital hypomyelinating neuropathy 17 0~~~4 41- ~ ~...

Journal of Neurology, Neurosurgery, and Psychiatry 1985;48: 1269-1276

Congenital hypomyelinating neuropathyYADOLLAH HARATI,* IAN J BUTLERt

From the Department ofNeurology, Baylor College ofMedicine and Veterans Administration MedicalCenter, * and the Departments ofNeurology and Pediatrics, University of Texas Health Science CenterMedical School at Houston, t Houston, Texas, USA

SUMMARY Two patients with congenital hypomyelinating neuropathy are reported with details ofsural nerve pathology. The resemblance of this condition to the hypomyelinating neuropathy ofTrembler mice is discussed and the pertinent medical literature reviewed.

Congenital hypomyelinating neuropathy is a severepolyneuropathy of early infancy manifesting ashypotonia, areflexia, distal muscle weakness andatrophy, and exceedingly slow nerve conductionvelocities, usually leading to early death or severedisability. The pathogenesis of this neuropathy is notclear. It has been stated that this neuropathy maydiffer from inherited hypertrophic neuropathy ofDejerine-Sottas type and from chronic inflam-matory polyneuropathy by the absence of typicalonion bulb formation and inflammation inperipheral nerve biopsy.

Case 1

A male child aged 3 years 10 months was evaluated formuscle weakness and wasting associated with delayedmotor development. He was born after a normal preg-nancy and delivery and is the only child of Mexican par-ents. His development appeared normal until the onset at 5months of a febrile illness associated with diarrhoea anddehydration and although the diarrhoea persisted for sev-eral months, he did not require hospital care. Routine vac-cinations had been performed, including triple vaccinationagainst poliomyelitis. At 21/2 years, he was evaluated in arural clinic for inability to crawl and walk. He was able tosit unsupported but upper and lower limbs were flaccid andthere was marked hyperextensibility at the joints withoutany contractures. He was encouraged to ambulate withlong leg braces and crutches and 6 months later he couldstand and walk with assistance. At age 3 years 10 monthshe was referred to a medical centre for diagnostic studies.He was an alert Spanish speaking child who cooperated

readily during the examination. He walked with the aid of

Address for reprint requests: Yadollah Harati, MD, Department ofNeurology, Baylor College of Medicine, 6501 Fannin, Houston,Texas 77030, USA.

Received 11 December 1984 and in revised form 2 May 1985.Accepted 10 May 1985

crutches and was unsteady on sitting unsupported. Therewas rigid thoracic scoliosis, marked wasting of all musclesand hyperextensibility of all limb joints (fig. 1). Muscleweakness was moderately severe, particularly in the legs.Sensation to pinprick and light touch appeared intact, deep

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Fig 1 Case 1. Able to stand with support.L269

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Fig 2 Sural nerve. Case 1. Longitudinal sections stainedfor modified Gomori's trichrome. Note hypercellulanity andabsence ofmyelinated nerve fibres. (x 195).tendon reflexes were absent and plantar reflexes were flex-or. Muscle and tongue fasciculations were not observedand peripheral nerves were not palpably enlarged. Neitherparent was available for examination or historical details.Routine blood and urine analysis was normal. Cerebrospi-

Fig 3 Sural nerve. Case 1. Note a few thin myelin (shortarrows) and amyelinated axons (long arrows). I ,An epoxysection, stained with toluidine blue. (x 360).

nal fluid analysis showed no red or white cells, glucose was40 mg/dl and protein was 58 mg/dl. Motor nerve conduc-tion velocity determinations for right median and peronealnerves were 2-6 and 2-1 m/s and terminal conductionlatencies were 18 and 23 ms respectively. Sensory action

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Fig 4 Sural nerve. Case 1. Electron micrograph. Normal size axons with no or very thin myelin sheath enclosed by emptybasement membrane (thin arrows). Double arrow points to a normal unmyelinated fibre. ('x 1700).

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potentials were unobtainable in right ulnar, median andsural nerves. Electromyography of right first dorsalinterosseus and tibialis anterior muscles showed no posi-tive sharp waves or fasciculations but motor unit potentialswere broad and of low amplitude.

Sural nerve biopsyDuring the surgical procedure, only a thread-like structurecould be seen in the usual location of the sural nerve pro-ximal to the lateral malleolus. No visible branch arose fromit. A 3 cm length of the thin nerve was removed anddivided into three segments for light microscopy, teasednerve fibre preparation and electron microscopy. Long-.4tudinal and transverse frozen unfixed sections werestained with H and E, modified Gomori trichrome, PAS,and cresyl violet. A segment was fixed in 2-5% glutaral-dehyde, post-fixed in 1% osmium tetroxide, dehydrated inalcohol and then embedded in Epon. Transverse sections,1 /±m thick, were stained with toluidine blue and 1,4 para-phenylenediamine for light microscopy. Ultra-thin sectionswere stained with uranyl acetate and lead citrate andexamined by electron microscopy.The third segment of the biopsy specimen was post-fixed

in 1% osmium tetroxide for 12 hours and placed in a mix-ture of glycerine and water for teasing.

Vastus lateralis muscle biopsyFor histochemical studies, tissue was frozen with liquid nit-rogen, and sectioned in a cryostat and stained with thefollowing methods: modified Gomori trichrome, NADH-TR, ATPase and pH 9-4 and succinic dehydrogenase.-

Results

No myelin was visualised on H and E and modifiedGomori trichrome stain. Marked hypercellularity ofendoneurium was present (fig. 2). No abnormaldeposits were present. In semi-thin sections the totalnumber of myelinated fibres were strikingly reducedand only a few very thinly myelinated axons wereseen scattered throughout the fascicles (fig. 3).There was no apparent loss of axons and the diame-ter of most axons was normal. Electron miroscopicexamination showed the absence of myelin in practi-cally all fibres (fig. 4). Exceptionally there was a thin

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Fig 6 Sural nerve. Case 1. Single teased nerve fibre showing an axon (long arrow) devoid ofmyelin sheath and severalSchwann cells faintly stained with osmium tetroxide (short arrows). (x 970).

myelin sheath composed of two to four lamellae.Atypical onion-bulbs formed only by a concentricarrangement of double-layered basement mem-branes separated by a narrow space were seen (fig5). These onion bulbs did not enclose Schwann cellcytoplasm. The axons in the centre of onion bulbswere of normal diameter and showed no structuralalterations. There was no evidence of myelin break-down. Schwann cell nuclei were normal. Unmyeli-nated Remak fibres were of normal diameter andshape and their density appeared normal.On teased fibre studies no myelin was detected

but several Schwann cells, faintly stained withosmium tetroxide were seen attached to the amyeli-nated axons (fig. 6). Muscle histochemistry revealeddenervation atrophy, hypertrophy of fibres and fibretype grouping indicative of reinnervation (fig 7). Nointramuscular nerve or muscle spindles were seen.

Case 2

A male child aged 3 years 11 months was evaluated fordelayed motor development and weakness. He was born toa healthy 24-year-old mother after a normal pregnancyand delivery and had no neonatal problems. He was slowto crawl and unable to walk until 22 months. His parentsbecame concerned at age 31/2 years when his 2-year-oldbrother surpassed him in motor development. The parentsstated that he could appreciate hot and cold sensations. Hispsychosocial and mental development were normal. Hehad chronic constipation requiring enemas. Routine vacci-

nations had been performed. His 2 year and 4 month oldbrothers were normal and parents were healthy with noevidence of neuromuscular disorders. He had normal men-tation and cranial nerve examination, but he was markedlyhypotonic. He could stand while supported and walkedwith a waddling gait. His proximal and distal musclestrength were 3/5. There were no muscle fasciculations ortongue fibrillations and peripheral nerves were not palp-ably enlarged. Mild distal muscle atrophy was present.Deep tendon reflexes were absent in lower extremities and1 + in upper extremities. Hot and cold sensation was intact.

Fig 7 Vastus lateralis muscle biopsy. Note central fasciclecomposed oftype 1 (darkly stained) fibres (fibre typegrouping) and enlarged type I and II fibres. NADH-TR.(x 200).

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Congenital hypomyelinating neuropathy

All laboratory tests including muscle enzymes, EKG,lipoprotein electrophoresis, and arylsulfatase A were nor-mal. CSF protein was 13 mg/dl. Sensory and motor nerveconductions of lower extremities could not be measured,but right ulnar nerve motor conduction velocity was 7-9ni/s. EMG of upper and lower limbs showed denervationwith fibrillations and positive waves and broad motor unitsnoted most prominently in the distal muscles of the upperand lower extremities. His two brothers were examinedand found to have no evidence of neuromuscular disorders.His parents were also normal on examination and by nerveconduction studies.A left vastus lateralis muscle biopsy specimen revealed

denervation change similar to those of Case 1. A suralnerve biopsy was performed and processed similar to Case1. A marked decrease in the number of myelinated fibreswith occasional middle-sized and small myelinated axonswere seen (fig 8). No typical onion-bulbs were seen but afew atypical bulbs composed of layers of reduplicatedbasement membrane were present. A few axons hadfilamentous hyperplasia and decreased neurotubules andmitochondria.

Discussion

In 1969 Lyon' reported a case of chronic progres-sive early infantile neuropathy whose nerve biopsyshowed virtual absence of myelin sheaths of myeli-nated fibres. Clinically, the patient had markeddelay of motor development, generalised musclehypotonia, weakness and atrophy of lower limbs,areilexia, and normal mental development, sensory

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and cranial nerve examination. His peripheralnerves were not palpably enlarged. The CSF proteinwas elevated and nerve conduction velocities wereunmeasurable. He termed this condition "earlyinfantile chronic neuropathy." Subsequently, othersimilar patients were reported using various termssuch as infantile polyneuropathy with defectivemyelination,2 hypertrophic interstitialpolyneuropathy in infancy,3 congenital hypo-myelinating neuropathy,4-8 chronic poly-radiculoneuropathy of infancy,9 and Dejerine-Sottasdisease.'0 Although the clinical presentation of thesecases were similar, the morphological abnormalitieswere not uniform. All showed severe loss of myelinsheath of myelinated fibres both in nerve biop-sies'410-12 or in necropsy material.29 In patientsreported by Karch,2 Ulrich,'2 Kasman,9 and Palix'2there were practically no onion bulbs, but patientsreported by Lyon,' Kennedy,4 Anderson,3 Moss,'0Towfighi,5 and Ono8 showed atypical onion bulbessentially composed of multiple layers of basementmembrane with little or no Schwann cell processes.There was no myelin breakdown product, and theaxons were preserved. In the first group, the chil-dren died in early infancy or early childhood whilethe second group, although severely handicapped,survived. Lack of evidence for an active myelinbreakdown, preservation of axons, and absence of awell formed Schwannian onion bulb and ademyelination-remyelination process, suggestedthat the cases of congenital hypomyelinating

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Fig 8 Sural nerve. Case 2. Longitudinal section. Note near total absence ofmyelinated fibres. Arrows point to a few remaining thinly myelinated axons. 1 ,uEpoxy sections. (x 420).



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Table Congenital hypomyelinating neuropathy: Summary of reported cases

Reference Age at onset Motor development Cranial Palpable CSF protein Nerve conduction velocites (NCV)nerves nerves

1 Early infancy Delayed, hypotonic Normal No 120 mg/dl Unmeasurable

4 Birth Delayed, hypotonic Normal Yes 90-190 mg/dl Less than 2-6 m/s

2 12 weeks Delayed, hypotonic Normal Not mentioned Not measured Unmeasurable

6 Birth Hypotonic Normal (?) Not mentioned 78 mg/dl "Extremely slow"

8 3 years 11 months Slow hypotonic Normal No 29 mg/dl Unmeasurable

5 Neonatal period Delayed, hypotonic Normal Not mentioned 344-484 mg/dl 13-24 m/s

7:Case I Birth Delayed, hypotonic Normal No 120 mg/dl Less than 5 m/s

Case II Birth Delayed, hypotonic. Normal No 97 mg/dl Less than 5 m/sswallowing difficulties

Case III Early infancy Delayed, walked at 5 Normal No 58 mg/dl Less than 5 m/syears

Case IV Early infancy Delayed Normal No 54 mg/dl Less than 5 mn/sPRESENTREPORTCase I 5 months Delayed, weakness Normal No 58 mg/dl Less than 2-6 rn/s

and hypotoniaCase II Early infancy Delayed, hypotonic Normal No 13 mg/dl Unmeasurable in legs. 7-9

in/sec of right ulnar nerve

neuropathy were different from typical Dejerine-Sottas disease. Based on these observations, it hasbeen hypothesised that in congenital hypomyelinat-ing neuropathy, there is a primary hypomyelinationof peripheral nerves secondary to a defect in theSchwann cells.4 This is in contrast to the demyelina-tion which occurs in Dejerine-Sottas disease. Ourobservation in two cases is in agreement with thishypothesis. Both patients had severe hypomyelina-tion, atypical onion bulb, and preserved axons.The concept of hypomyelination implies a congen-

ital onset and a nonprogressive or slowly progressivecourse unless axon degeneration intervenes. In fact,the disease may start as early as the time of birth. Acase reported by Hakamada6 was born with a lowApgar score and respiratory distress. He hadextreme hypotonia with contraction of all fourlimbs. His sural nerve biopsy performed at onemonth of age showed absence of myelin sheath, wellpreserved axons, and no onion bulb formation ormyelin debris. There were decreased fetal move-ments during the pregnancy suggestive of anintrauterine onset. The case reported by Karch2 wasevaluated at the age of 12 weeks because of feedingdifficulties. He had mild initial improvement but

died at age 18 months of respiratory insufficiency.The necropsy revealed total absence of myelin in thecranial and spinal nerve roots distal to the glio-Schwannian junction. The brain was normallymyelinated and the spinal cord showed no abnor-malities. The other reported cases which are sum-marised in the table also had their onset in earlyinfancy, and at the time of report, most were alive,although severely handicapped.

All reported cases, except the patient reported byOno8 and our own case 2, had elevated CSF proteinand very slow or unmeasurable nerve conductionvelocity. Despite the extremely low nerve conduc-tion velocity, the functional incapacity in thesepatients is less than might be expected. Both of ourpatients, for example, could walk with assistance.The similarities of human congenital

hypomyelinating neuropathy to the neuropathy ofTrembler mouse is striking.'3 The Trembler mutantmouse has a dominantly inherited neuropathycharacterised by the presence of abnormally thinmyelin sheaths, absence of axonal loss, and slowperipheral nerve conduction velocity. The deficit inmyelination is limited to the peripheral nerves, ispresent at the time of birth, and is associated with an

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Congenital hypomyelinating neuropathy

Muscle biopsy Nerve pathology Prognosis Other

Not performed Absence of myelin, atypical onion Alive at 30 monthsbulbs, preserved axons

Absent myelin of intramuscular Absent myelin sheath. Onion bulbs and Alive at 55 y Slight reduced NCV in mother.nerves, Type I fibre predoniinance empty basement membrane. Preserved 10-month old sister with slow

axons. No myelin debris developmentNot performed Necropsy: Absence of myelin, no onion Initial mild improvement. Died -

bulb, axonal loss at 18 monthsType II fibre predominance and Near total absence of myelin sheath. Died at 4 months -

atrophy. Slight denervation Preserved axon. No onion bulbs. Nomyelin debris

Absent myelin of intramuscular Absence of myelin. Increased Alive at 5 years -

nerves. Type II fibre Schwann' s cell nuclei. Preserved axons.predominance No myelin debris

Group atrophy Sural nerve biopsy: Thinly myelinated Died at 39 months Possible similar affected sibling.axons. Preserved axons. Occasional Normal NCV & EMG of parents.atypical onion bulbs. Necropsy: Same Presence of glial bundles atfindings for cranial nerves and spinal spinal and cranial nerve rootsroots

Not examined Absence of myelin. Reduplicated Alive at 30 monthsbasement membrane (atypical onionbulbs). Rare typical onion bulbs.Preserved axons. No myelin debris

Group atrophy Same as Case I Alive at 6 years

Normal Absence of myelin in 50% of fibres. Alive at 5 yearsVery thin myelin in others. Atypicalonion bulbs. Preserved axons. Nomyelin debris

Group atrophy Same as Case III Alive at 9 years

Denervation-reinnervation Absent myelin. Preserved axon. No Alive at 5 yearsonion bulbs

Denervation Myelin loss. Atypical onion bulbs. No Alive at 4 yearsmyelin debris

exaggerated rate of Schwann cell proliferation whichpersists into adulthood. The remarkable nervetransplantation experiments by Aguayo et al.I314have demonstrated that in Trembler mouse theneuropathy is due to a primary Schwann cell disor-der. Segments of sciatic nerves from Trembler micewere grafted into sciatic nerves of normal mice andvice versa. In each instance, the regenerated axonstook on the morphological appearance of the donornerve. Thus, regenerating axons in the normalmouse growing into the segment grafted fromTrembler nerve did not myelinate, whereas theTrembler axons growing into the segment graftedfrom normal nerve developed nearly normal myeli-nation. A similar experiment, involving transplanta-tion of nerve biopsy obtained from patients withcongenital hypomyelinating neuropathy into the sci-atic nerves of normal, immunosuppressed mice,have not been performed. Transplantation of abiopsy specimen of sural nerve of a patient withCharcot-Marie-Tooth disease into normal butimmunosuppressed mice have shown failure ofCharcot-Marie-Tooth Schwann cells to myelinatemouse axons.'5 The same results may be predictedfrom studies on congenital hypomyelinating

neuropathy.The disparity between the degree of slowed nerve

conduction and functional impairment in patientswith congenital hypomyelinating neuropathy is notfully explained. It is possible that nodal and para-nodal membrane specialisation required for normalsaltatory nerve conduction is not fully developed inthe peripheral nerves of these patients. In normalmature peripheral nerve, the freeze fracture techni-ques have demonstrated that the putative sodiumchannel particles, thought to participate in saltatoryconduction velocity, are more confined to the nodesof Ranvier than the axolemma.5-7 Amyelination ordemyelination may result in uniform distribution ofthese channels and development of continuous con-duction along the axon. Although freeze fracturestudies of the nerve biopsies of patients with congen-ital hypomyelinating neuropathy have not been per-formed, experiments in animals with primary myelindeficiency indicate that the absence of myelin affectsthe concentration of particles presumed to besodium channels at the nodes of Ranvier.'8 Finally,in view of the sporadic nature of most of thereported cases it is possible that like Trembler micethese cases are also a new dominant mutation.

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Dr V Bagherian and D Armstrong assisted in elec-tron microscopy of Case 1.

References

'Lyon G. Ultrastructural study of a nerve biopsy from acase of early infantile chronic neuropathy. ActaNeuropathol (Berl) 1969; 13:131-42.

2 Karch SB, Urich H. Infantile polyneuropathy with defec-tive myelination: an autopsy study. Dev Med ChildNeurol 1975; 17:504-11.

3 Anderson RM, Dennett X, Hopkins IJ, Shield LK.Hypertrophic interstitial polyneuropathy in infancy:clinical and pathologic features in two cases. J Pediatr1973;82:619-24.

4 Kennedy WR, Sung JH, Berry JF. A case of congenitalhypomyelination neuropathy: Clinical, morphological,and chemical studies. Arch Neurol 1977;34:337-45.

s Towfighi J. Congenital hypomyelination neuropathy:Glial bundles in cranial and spinal nerve roots. AnnNeurol 1981;10:570-3.

6 Hakamada S, Kumagai T, Hara K, Miyazakis. Congeni-tal hypomyelinating neuropathy in a newborn.Neuropediatrics 1983; 14:182-3.

7 Guzzetta F, Ferriere G, Lyon C. Congenital hypomyeli-nation polyneuropathy. Brain 1982; 105: 395-416.

8 Ono J, Senba E, Okada S, et al. A case report of congeni-tal hypomyelination. Eur J Pediatr 1982; 138:265-70.

9 Kasman M, Bernstein L, Schulman S. Chronicpolyradiculoneuropathy of infancy; a report of threecases with familial incidence. Neurology (Minneap)1976;26:565-73.

10 Moss RB, Sriram S, Kelts KA, Forno LS, Lewiston NJ.Chronic neuropathy presenting as a floppy infant with

Harati, Butler

respiratory distress. Pediatrics 1979;64:459-64.Palix C, Coignet J. Un cas de polyneuropathie

peripherique neo-natale par amyelinisation. Pediatrie1978;33:201-7.

12 Ulrich J, Hirt HR, Kleihues P, Oberholzer M. Connatalpolyneuropathy. A case with proliferatedmicrofilaments in Schwann cells. Acta Neuropathol(Berl) 1981;55:39-46.

3 Aguayo JA, Attiweli M, Trecarten J, et aL A binormalmyelination in transplanted Trembler mouse Schwanncells. Nature 1977;265:73-5.

4 Aguayo JA, Perkins S, Duncan I, Bray G. Human andanimal neuropathies studied in experimental nervetransplant. In: Canal N, Pozza G, eds. PeripheralNeuropathies. Elsevier/North Holland BiomedicalPress 1978:37-48.

Livingston RB, Pfenninger K, Moore H, Akert K.Specialized paranodal and internodal glial-axonaljunctions in the peripheral and central nervous sys-tem: a freeze-etching study. Brain Res 1973;58: 1.

16 Rosenbluth J. Intramembranous particle distribution atthe nodes of Ranvier and adjacent axolemma inmyelinated axons of the frog brain. J Neurocytol1976;5: 731.

7 Schnapp B, Mugnaini E. The myelin sheath: Electronmicroscopic studies with thin sections and freeze frac-ture. In: Santini M, ed. Golgi Centennial SymposiumProceedings. New York: Raven Press 1975:209.

Rosenbluth J. Freeze fracture studies of nerve fibers:Evidence that regional differentiation of theaxolemma depends upon glial contact. In: Aguayo AJ,Karpati G, eds. Current Topics in Nerve and MuscleResearch. Amsterdam: Excerpta Medica 1979:200-9.



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