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Diagnosis of infantile neuroaxonal dystrophy by skin biopsy.

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Diagnosis of Infantile
Neuroaxonal Dystrophy
by Skin Biopsy
Krystyna Wisniewski, M D , PhD,
and Henry M. Wisniewski, MD, P h D
Skin biopsy w i t h ultrastructural examination of cutaneous nerves showed dystrophic axons (spheroids),
confirming a diagnosis of infantile neuroaxonal dystrophy. Independent of axonal changes, a f e w endoneurial and Schwann cells showed cytoplasmic inclusion bodies composed o f structures similar to those
seen i n the spheroids.
Wisniewski K, Wisniewski HM:
Diagnosis of infantile neuroaxonal
dystrophy by skin biopsy.
Ann Neurol 7:377-379, 1980
The diagnosis of infantile neuroaxonal dystrophy
(INAD), or Seitelberger disease, was established in
1952 [7]. It is characterized primarily by pathological
features seen in the complete neuraxis. At present,
the cause of the disease and pathogenesis of the
axonal changes remain unknown [l-81. In this paper
we report that the diagnosis of INAD can be made
from cutaneous nerves obtained from skin biopsy.
Material and Method
A 5-year-old girl with a history of slowly progressive nervous disease was studied. She was the product of the
mother’s seventh pregnancy. H e r birth weight was 3.2 kg.
Developmental milestones were normal up to the age of
1% years. She was able to say words at 8 months and short
sentences at 14 months, sat at 9 months, and walked at 16
months. After 1% years of age she showed regression in
motor, language, and social adaptive areas. By the age of
234 years the patient was functioning at a 29’2 month level
and at 3y2 years at less than a 1 month level in all areas.
The physical examination was within normal limits except for height of 99 cm, weight of 12.3 kg, and head circumference of 4 9 cm, all below the third percentile. O n
neurological examination the patient was alert but did not
respond to auditory or visual stimuli. Cranial nerves I1 to
XI1 were grossly intact except for bilateral optic atrophy,
horizontal nystagmus with a fast component on lateral gaze,
From the New York State Institute for Basic Research in Mental
Retardation, Staten Island, and the Departments of Neurology and
Pathology, Downstate Medical Center, Brooklyn, N Y 11203.
Accepted for publication Aug 19, 1979.
Address reprint requests to Dr Krystyna Wisniewski, Institute for
Basic Research in Mental Retardation, 1050 Forest Hill Rd, Staten
Island, N Y 10314.
and positive jaw reflexes. MuscIe tone was somewhat decreased, with fixed contractures of the ankle joints. N o
spontaneous movements were seen in the extremities,
which were in flexion. Occasionally during myoclonic seizures the upper extremities were extended. Deep tendon
reflexes were 3+ and there were bilateral extensor plantar
responses. Facial dyskinesia was occasionally seen. Frontal
release signs were present, and there was some distal muscle atrophy in her extremities. We were unable to
examine the coordination system. She reacted poorly to
pain; other sensory signs could not be tested. Ciliospinal
reflexes were present. Arylsulfatase, galactocerebrosidase,
and hexosaminidase in the leukocytes were normal. The
electroencephalogram showed multifocal spike and slow
wave activity. Results of cerebrospinal fluid studies were
normal. Nerve conduction studies show motor and sensory
pol y neuropath y .
The past medical history was unremarkable except for
myoclonic seizures since 2$5 years of age and occasional
grand ma1 seizures since 4 years. The patient was of
Chinese descent. There was no consanguinity. Two older
siblings (male and female) had died at 6 and 9 years of age,
respectively, and showed an identical clinical course and
symptoms to the patient. Autopsy of the patient’s 6-yearold brother showed typical pathological changes of I N A D
in the central nervous system; autopsy of the sister was not
permitted. An older sibling, now 15, is doing well. The
mother’s other pregnancies included two abortions and one
stillbirth. There is no history of mental retardation on the
paternal o r maternal side.
Blocks of tissue (2 mm specimens from the skin
biopsy and sural nerve biopsy) were placed directly into a
solution of 5’9%glutaraldehyde buffered in 0.1 M phosphate buffer at p H 7.4 for two hours. They were then fixed
in phosphate-buffered 1% osmium, followed by rapid dehydration using a series of graded alcohols and propylene
oxide. Subsequently, the blocks were infiltrated and embedded in araldite. Silver sections were cut and mounted
on Formvar-coated and uncoated copper grids and were
stained with uranyl acetate and lead citrate. Micrographs
were taken on a Hitachi H V 1 I E l .
Electron microscopic examination of the skin biopsy
specimen showed typical spheroids in severely dystrophic axons in the cutaneous nerve bundles (Figure, parts 1-5). The dystrophic axons were identical
to those seen in central and peripheral nervous tissue
in patients with INAD. They showed pleomorphic
structures, neurotubules, vesicular membranous
profiles, abundant filamentous material, vacuoles,
patchy dense material, granular multigranular bodies,
glycogen accumulation, macromitochondria, and
layered loops of membranes. The membranous and
tubular profiles in the spheroids were the most
prominent features. The pathological changes in the
cutaneous nerves were not generalized and were seen
only in unmyelinated nerve fibers, while in the sural
0364-5134/SOIO4O377-O~$Ol.25@ 1978 by Krystyna Wisniewski
( 1 ) Cutaneous nerve bundle. In only one unnzyelinated nerzv
fiber was an early state o f accumulation o f z~esiculotubularprojiles noted. This axon is not yet enlarged. ( ~ 3 0 , 0 0 0 (. )2 ) Cutaneous newe shouis many dystrophic large axons (spheroids)
accumulated in the vesiculotubular profiles. This profile is more
adzlanced than that in 1. (X35,OOO.) ( 3 )Tuio typical
spheroids in the cutaneous newe bundle, filled ulith mem) Cubranotubularprojiles and a few vacuoles. ( ~ 3 0 . 0 0 0 . (4)
taneous newe bundle containing one large spheroid filled with
dense[?)packed membranotubular structures. ( X 15,000.) ( 5 )
Two spheroids in one nerve bundle, one composed of menzbranogranularprofiles, the other with tubulogranular projiles.
( ~ 2 5 , 0 0 0 .(
)6)Endoneurial cells filled with c.ytoplasn2ic inclusions containing similar profiles as the spheroids. ( a
X30,OOO: b X6,OOO.)
Annals o f Neurology
N o 4 April 1980
files without enlargement of their diameter (Figure,
part 1).
Few endoneurial and Schwann cells, mainly in the
sural nerve biopsy, ‘showed cytoplasmic inclusion
bodies filled with material similar to that seen in the
dystrophic axons (Figure, part 6). The other elements
of the skin were unchanged.
Skin biopsy is a simple technique used for the diagnosis o i many storage diseases. I N A D can be diagnosed with skin biopsy. Cutaneous nerve bundles
must be investigated carefully by electron microscopy for dystrophic axons. This is especially true in
patients suspected to have INAD (slowly progressive
neurological disease with upper and lower motor
neuron dysfunction, with or without a positive family
history and negative results for lysosomal disease).
The spheroids which we found in unmyelinated
nerve fibers were similar to those described recently
by Arsenio-Nunes and Goutieres [ll in biopsies of
the conjunctiva and by Martin et a1 [6] in biopsies of
the conjunctiva and skin. We also found abnormal
cytoplasmic inclusion bodies in a few endoneurial
and Schwann cells. Inclusions in Schwann cells in
I N A D were described in a nerve biopsy by Yagishita
et a1 [9];homLver, their presence in endoneurial cells
is a new observation.
nerve biopsy the pathological changes were seen in
both myelinated and unmyelinated fibers. Some
had Only One dystrophic axon; Others
contained three or more (Figure, parts 2-5). Some
axons showed accumulation of vesiculotubular pro-
1. Arsenio-Nunes ML, Goutieres F: Diagnosis of infantile
neuroaxonal dystrophy by conjunctival biopsy. J Neurol
Neurosurg Psychiatry 41:511-515, 1978
2. Berard-Badier M, Gambarelli D, Pinsard N , et al: Infantile
neuroaxonal dystrophy or Seitelberger’s disease. Acta Neuropathol (Berl) suppl 5:30-39, 1971
3. Herman MM, Huttenlocher PR, Bensch KG: Electron microscopic observations in infantile neuroaxonal dystropny. Arch
Neurol 20:19-34, 1969
4. Lampert PW: A comparative electron microscopic study of
reactive, degenerating and dystrophic axons. J Neuropathol
Exp Neurol 26:345-368, 1967
5. Lu HM, Larson M, Misuno Y:An analysis of the ultrastructural
findings in infantile neuroaxonal dystrophy (Seitelberger’s disease). Acta Neuropathol (Berl) 27:201-213, 1974
6. Martin JJ, Leroy JG, Libert J, et al: Skin and conjunctival biopsies in infantile neuroaxonal dystrophy. Acta Neuropathol
(Berl) 45:247-251, 1979
7. Seitelberger F Eine unbekannte Form von infantiler Lipoidspeicher-Krankheit des Gehirns. Proceedings of the First Congress on Neuropathology. Turin, Rosenberg and Sellier, 1952,
VOI 3, PP 323-333
8. Seitelberger F, Jellinger K: Neuroaxonal dystrophy and
Hallervorden-Spatz disease, in Goldensohn ES, Appel SH
(eds): Scientific Approaches to Clinical Neurology. Philadelphia, Lea & Febiger, 1977
9. Yagishita S, Itoh Y , Nakano T, et al: Infantile neuroaxonal
dystrophy. Schwann cell inclusion in the peripheral nerve. Acta
Neuropathol (Berl) 41:257-259, 1978
Brief Communication: Wisniewski and Wisniewski: INAD Diagnosis by Skin Biopsy
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biopsy, infantile, skin, diagnosis, dystrophy, neuroaxonal
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