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Neurology India
Medknow Publications on behalf of the Neurological Society of India
ISSN: 0028-3886 EISSN: 1998-4022
Vol. 53, Num. 3, 2005, pp. 339-341
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Neurology India, Vol. 53, No. 3, July-September, 2005, pp. 339-341
Case Reports
Neurological manifestations of Ehlers-Danlos syndrome
Mathew T, Sinha S, Taly AB, Arunodaya GR, Srikanth SG
Departments of Neurology, National Institute of Mental Health and Neurosciences, Bangalore
Correspondence Address:National Institute of Mental Health, Bangalore - 560
029, abtaly@yahoo.com
Date of Acceptance: 23-May-2005
Code Number: ni05119
Abstract
Ehlers-Danlos Syndrome (EDS) is more identified for its cutaneous features but its neurological manifestations have not received the focused attention. Four patients of Ehlers-Danlos Syndrome (EDS) with neurological manifestations were evaluated for phenotypic data. These four men were from three families and two had consanguineous parentage. The mean age at onset and presentation of neurological symptoms were 10.5 years and 19 years respectively. Patient 1 presented with bilateral optic atrophy, sensorineural deafness, cerebellar ataxia and neuropathy. Patient 2 had marfanoid habitus, chorea and cerebellar ataxia. Patient 3 had action and percussion myotonia, wasting and weakness of sternocleidomastoid and distal limb muscles. Patient 4 had action myotonia, mirror movements of both hands and neuropathy. MRI of brain showed right parietal polymicrogyria. Neuroaxis involvement at multiple levels in EDS may have prognostic significance.
Keywords: Ataxia, chorea, Ehlers-Danlos syndrome, mirror
movement, myotonia, neurological manifestations, and polymicrogyria.
Introduction Ehlers-Danlos syndrome (EDS) is a generalized connective tissue disorder, characterized by skin fragility, skin hyperextensibility and joint hypermobility and may affect any part of the neuroaxis.[1] Cerebrovascular complications are coμn and other neurological manifestations are rare.[2] We report four patients of EDS with neurological manifestations other than cerebrovascular complications.
Case History
These four patients clinically diagnosed EDS were evaluated from 1998 to 2002. Their phenotypic data, family pedigree and imaging features are described.
Patient 1
A 20-year old man, presented with delayed motor milestones and unsteady
gait since early childhood. He was born of a second-degree consanguineous
parentage. There was no similar illness in family. He had hyperextensible
joints, hyperelastic skin, pes planus, scoliosis, left facial hemiatrophy,
primary optic atrophy and sensorineural deafness, distal limb weakness,
hyporeflexia, flexor plantar response and impairment of vibration sense
in toes and impaired tandem gait. Complete hemogram and routine biochemical
tests including serum creatine kinase (CPK) were normal. Nerve conduction
(NC) study showed evidence of demyelinating motor-sensory neuropathy.
Magnetic resonance imaging (MRI) of brain was normal. Visual evoked responses
were not recordable bilaterally. Sural nerve biopsy showed focal loss
of large diameter fibres and evidence of demyelination. Diagnosis of
EDS with optic atrophy, deafness, demyelinating neuropathy and cerebellar
ataxia was considered.
Patient 2
This 22-year old man manifested with swaying while walking, slurring
of speech, involuntary movements and fatigability for 2 years. There
was no history of similar illness in the family. He had marfanoid habitus,
curly hair, progeria, hyperextensible joints and hyperelastic skin, scanning
speech, chorea involving all limbs, in-coordination of extremities and
impaired tandem gait. Routine hemogram and biochemical examinations including
serum CPK, copper, ceruloplasmin, thyroid function test and CSF analysis
were normal. Nerve conduction studies and multimodal evoked responses
did not reveal any abnormality. MRI brain showed cerebellar and brainstem
atrophy [Figure - 1].
Genetic analysis was not performed. A diagnosis of EDS with chorea and
cerebellar ataxia was made.
Patient 3
This 15-year old boy reported with progressive proximal weakness
and difficulty in releasing handgrip of 5 years duration. He was born
pre-term (7th month of gestation) to consanguineous parents. His elder
brother (Case 4) had similar illness. He had hyperelastic skin [Figure - 2]A,
hyperextensible joints with positive thumb and wrist sign, ′cigarette paper ′like
scars on the right knee and pes cavus deformity. There was wasting of
sternocleidomastoid, forearm and intrinsic muscles of the hand, and hypertrophy
of calf and extensor digitorum brevis muscles. Most remarkable was percussion
- and action myotonia [Figure - 2]B
in all muscles of the limbs, facial musculature and tongue. Minimal weakness
(MRC grade: 4/5) was present, but was more in distal muscles. Muscle
stretch reflexes were diminished in the upper limbs and normal in the
lower limbs. Plantar response was flexor. There was no evidence of frontal
baldness, cataract, gynaecomastia or testicular atrophy. Hemogram, routine
biochemical tests and serum CPK were normal. NC study was normal. Electromyography
revealed a myopathic pattern with typical myotonic discharges. Left biceps
muscle biopsy showed features suggestive of mild neurogenic atrophy.
A diagnosis of EDS type 1 with an associated myotonic disorder was established.
Patient 4
A 19 year old boy, elder brother of Patient 3, presented with minimal
difficulty in releasing objects from the left hand for 4 years, mild
difficulty in standing from sitting position, mirror movements of hands
and occasional falls while walking for past 11 years. He had short
neck, hypopigmented areas over scalp, keloid scars over shoulder and
chest,
high arched palate, periodontitis, hyperextensible joints, hyperelastic
skin, positive thumb and wrist sign, Cigarette paper scars over both
knees, right lower limb wasting and pes planus. He had wasting of bilateral
forearm and intrinsic muscles of hand and left hand action myotonia
but no percussion hypotonia. Mirror movements in both hands were evident.
There were no other deficits. Hemogram and biochemical investigations
including serum CPK and T3, T4, TSH were normal. NC study showed reduced
compound muscle action potential in right median (5.52 mV) and ulnar
(4.94 mV) nerves with preserved conduction velocity and normal parameters
in the lower limbs. Electromyography revealed myotonic discharges.
MRI
(brain) revealed right parietal polymicrogyria [Figure - 3].
MRI (cervical spine) showed insignificant lateral displacement of odontoid
to the left. A diagnosis of EDS with mirror movements, polymicrogyria
and axonal neuropathy was considered.
Discussion
Ehlers-Danlos syndrome constitutes a group of connective tissue disorders characterized by clinical and genetic variability.[3] Mutations in 8 separate genes contribute to these phenotypes. Earlier reports were focused on the skin and ocular abnormalities. The heterogeneity began to be appreciated in the past few decades, from the insights gained from biochemical and molecular genetic studies.[1]
Ehlers-Danlos
syndrome type 1 has an autosomal dominant inheritance and affected individuals
have soft, velvety, hyperextensible skin, joint hypermobility, easy bruisablility
and thin, atrophic ′cigarette-paper′ scars following trauma. About 50% of
the infants with EDS 1 are born 4 to 8 weeks prematurely because of the
fragile fetal membranes as in our Patient 3. [1] Neurological manifestation other than stroke and hypotonia include peripheral neuropathy,[4] epilepsy,[5] neuronal migration disorders,[3],[6] Melkerson - Rosenthal syndrome,[7] familial spastic ataxia[8] and dentatopallido luysian atrophy.[9] EDS has a prevalence of 1 in 10,000 persons. It is therefore possible that these neurological illnesses coexist rather than causally linked.[1] In the present series rare manifestations like neuropathy, optic atrophy, deafness, cerebellar ataxia, chorea, myotonia, calf hypertrophy, polymicrogyria and mirror movements were noted. Patient 2 had chorea, ataxia and cerebellar/ brainstem atrophy raising a possibility of co-occurrence of DRPLA. Similarly Patients 3 and 4 had features of myotonia. However genetic analysis could not be carried out in them.
Defects in extra cellular matrix proteins have been proposed as a mechanism
for arterial aneurysms and EDS IV.[10] Disruption
between the extracellular matrix and cytoskeleton causes aberrations
in cellular migration. This might result in various congenital malformations
of the brain parenchyma like neuronal migration disorders.[5] The
extracellular matrix proteins involved may affect collagen or tenascins,
a family of glycoproteins expressed in the surface of neurons and glial
cells.[6] Mice deficient in
small leucine rich proteoglycans develop osteoporosis, EDS, muscular
dystrophy and corneal diseases. This may be the link between some cases
of muscular dystrophy and EDS.[11]
Ehlers-Danlos syndrome may affect all level of neuraxis. A careful
search may reveal asymptomatic and unrecognized abnormalities, which
offer better
explanations for the patient′s symptoms and may alter prognosis.
References
1. | Byers PH. Disorders of collagen biosynthesis and structure. In: Scriver CR, Beaudet AL, Sly WS, Valle D, editors. The Metabolic and molecular bases of inherited disease. 7th ed. New York: McGraw Hill; 1995;5241-71. Back to cited text no. 1 |
2. | Pretorius ME, Butler IJ. Neurologic manifestations of Ehlers-Danlos syndrome. Neurology 1983;33:1087-89. Back to cited text no. 2 [PUBMED] |
3. | Thomas P, Bossan A, Lacour JP, Chanalet S, Ortonne JP, Chatel M. Ehlers-Danlos syndrome with subependymal periventricular heterotopias. Neurology 1996;46:1165-67. Back to cited text no. 3 [PUBMED] |
4. | Muellbacher W, Finisterer J, Mamoli B, Bittner RE, Trautinger F. Axonal neuropathy in Ehlers -Danlos syndrome. Muscle Nerve 1998; 21:972-4. Back to cited text no. 4 |
5. | Jacome DE. Epilepsy in Ehlers - Danlos Syndrome. Epilepsia 1999;40:467-73. Back to cited text no. 5 [PUBMED] |
6. | Echaniz-Laguna A, de Saint-Martin A, Lafontaine A L, Tasch E, Thomas P, Hirsh E et al. Bilateral Focal Polymicrogyria in Ehlers - Danlos syndrome. Arch Neurol 2000;57:123-7. Back to cited text no. 6 |
7. | Caksen H, Cesur Y, Tombul T, Uner A, Kirimi E, Tuncer O et al. A case of Melkersson-Rosenthal syndrome associated with Ehlers - Danlos syndrome. Genet Couns 2002;13:183-6. Back to cited text no. 7 |
8. | Chouza C, Caamano JL, De Medina O, Bogacz J, Oehninger C, Vignale R et al. Familial spastic ataxia associated with Ehlers-Danlos syndrome with platelet dysfunction. Can J Neurol Sci 1984;11:541-549. Back to cited text no. 8 |
9. | Sugie K, Nakamuro T, Harada N, Suzumura A, Takayanagi T. A report of two siblings with both maternal dentate-rubro - pallido - luysian atrophy and paternal Ehlers - Danlos syndrome type III. Rinsho Shinkeigaku 1998;38:233-7. Back to cited text no. 9 [PUBMED] |
10. | North KN, Whiteman DAH, Pepin MG, Byers PH. Cerebrovascular complications in Ehlers-Danlos syndrome type IV. Ann Neurol 1995;38:960-4. Back to cited text no. 10 |
11. | Ameye L, Young MF. Mice deficient in small leucine - rich proteoglycans: novel in vivo model for osteoporosis, Ehlers - Danlos syndrome, muscular dystrophy and corneal disease. Glycobiology 2002;12:107-16 Back to cited text no. 11 [PUBMED] [FULLTEXT] |
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