close

Вход

Забыли?

вход по аккаунту

?

Chronic leigh disease A genetic and biochemical study.

код для вставкиСкачать
Chronic Leigh Disease:
A Genetic and Biochemical Study
Andreas Plaitakis, MD, William 0. Whetsell, Jr, MD,” Jack R. Cooper, PhD, and Melvin D. Yahr, M D
The large family of a 21-year-old man who died of Leigh disease was investigated for evidence of neurological
abnormalities and presence of the adenosine triphosphate-thiamine diphosphate phosphoryltransferase inhibitor
factor. Of 217 persons (seven generations) included in the pedigree, 68 were examined neurologically and biochemically. Fourteen (20%), 5 of whom had abnormal neurological findings, were found to excrete the inhibitor
factor. Clinical manifestations varied from severe neurological affliction to subtle deficits. A chronic relapsing
course was frequently encountered, with exacerbations occurring in association with apparent metabolic stress.
Parental consanguinity was identified in the propositus as well as in other family members with neurological abnormalities. Males and females were affected, and no vertical transmission of the trait was found. These multigenerational data suggest that Leigh disease in adults is inherited in an autosomal recessive manner and has variable
degrees of expression with a wide spectrum of neurological manifestations.
Plaitakis A, Whetsell WO Jr, Cooper JR, et al: Chronic Leigh disease: a genetic and biochemical study.
Ann Neurol 7:304-310, 1980
Subacute necrotizing encephalomyelopathy (SNE),
originally described by Leigh in 1751 [12], has been
largely considered a familial degenerative neurological disorder of infancy and early childhood that usually has a fatal outcome within two years [17]. In recent years a few adults with SNE have been identified
by postmortem examination [6, 13, 23-25]. In these
patients, an acute o r subacute illness developed
either without antecedent clinical symptoms [6, 131
o r following longstanding neurological involvement
[6, 23-25]. Because of the paucity of data from adult
patients, there are no known criteria, except duration
of the disease, which can be used to distinguish an
“adult form” from a “childhood form” of SNE [23,
251.
Although the pathogenesis of the disorder is not
yet fully elucidated, a disturbance in thiamine metabolism has been implicated. Cooper e t a1 [3] demonstrated, in body fluids (urine, blood, and spinal fluid)
of patients affected by the disease, a factor which inhibits adenosine triphosphate (ATP)-thiamine diphosphate (TDP) phosphoryltransferase, thus blocking the synthesis of thiamine triphosphate. Urine
assay of the inhibitor factor has been utilized as a diagnostic test for the disease [4, 171. In addition, it
has been used t o identify some, but not all, obligate
carriers [15, 171. Though the assay has been helpful
in identifying high-risk families, false positive and
false negative results occur [17, 201.
We recently reported a patient who died of Leigh
disease at 2 1 years of age, and we presented evidence
that the TDP-ATP phosphoryltransferase inhibitor
factor was present in members of his immediate family [25]. Because the patient came from a small, isolated Greek island with a total population of 1,200,
we were presented with the unusual opportunity of
investigating an inbred, high-risk population from
which Leigh disease in an adult had been documented. A pedigree covering 2 17 family members of
the propositus (seven generations) was constructed;
68 of the family members were evaluated neurologically, and their urine was tested for presence of the
inhibitor factor. The clinical characteristics of family
members with neurological abnormalities and results
of urine assays are detailed in this report. The role of
genetic, biochemical, and exogenous factors in the
development of SNE and their effect on the natural
history of the disease are considered.
From the Department of Neurology, Mount Sinai School of Medicine Of the City University Of New
New
NY, and the
Department of Pharmacology, Yale University School of Me&cine, New Haven, CT.
Accepted for publication July 28, 1779.
Address reprint requests
Dr plaita&, Departmentof Neuralogy, M~~~~s i n i School ofMedicine, Fifth
at tooth st, N~~
York, N Y 10029.
Methods
A pedigree for the propositus, covering seven generations,
encompassed 2 17 other family members (Figure), 111
*Present adclrcss: Division of Neuroparhology, Department of
Pathology, University of Tennessee School of Medicine, Mem
phis, T N 38163.
304 0364-5 134/80/040304-07$01.25@ 1978 by Andreas Plaitakis
u
l
0
w
5
5
2
Ages (years) are indicated
below the symbol
6 8 Number ofsiblings
positive
B @equivocal
Inhibitor foctor
ASYMPTOMATIC
0 0 negative
17
1 Individuals personally examined
8
I
T
P Propositus
w
Pedigree for the propositus and 21 7 family members (seven
generations). Living family members with neurological abnormalities and presence of the inhibitorfactor (considered t o be
affected or possibly affected) are as follows: V-37, V1-40,
VI-68, VII-9, VII-14. Deceased family members who manifested neurological illness compatible with SNE (possibly affected) are as follows: IV-20, V-38, V-39, VI-27, and VI-62.
IV
I11
I1
I
Inhibitor factor
D O negative
positive
equivocal
N EURO LOGlCA LLY
ABNORMAL
DECEASED
No neurological illness
10
Possibly affected
(probably not affected)
@,$If Neurological illness present
pl#
,d# Affected
9
4
Incidence of Inhibitor Factor in Family Members
Inhibitor Factor
Clinical Status
No. of
Persons
Asymptomatic
Neurologically
abnormal
61
Total
68
Positive
Equivocal
(340%)
(25-4096)
9
5 (p < 0.001)
7
14
men and 106 women. Sixty-eight of 168 living family
members were examined neurologically by one of us, and
their urines were studied for the presence of inhibitor factor. Specimens collected on the island were dried ( 5 ml) on
filter paper ( 5 x 5 cm) and immediately mailed to our laboratory for biochemical analysis. Urine samples were also
collected from family members living in New York City
and were frozen and stored for assay. All urine specimens
were numbered, and no identifying information was
supplied to laboratory personnel prior to assay. Information regarding the 40 deceased family members was obtained from close relatives, from the practicing physician
on the island, and from institutions in which some of these
individuals were hospitalized or followed as outpatients.
Results
S e v e n family m e m b e r s among the 68 evaluated clinically w e r e f o u n d t o have abnormalities on neurological examination. Of these, 4 w e r e children (ages 8 t o
12), 1 was a n adolescent (age 17), a n d 2 were adults
(ages 47 and 50). I n 5 of t h e s e 7 family m e m b e r s t h e
o n s e t of neurological manifestations d a t e d from infancy or early childhood. The neurological illness had
a chronic remitting c o u r s e in a t least 3 individuals.
N o n e of t h e patients examined had evidence of active progression of neurological involvement at t h e
time of this study.
U r i n e assays s h o w e d t h e TDP-ATP phosphoryltransferase inhibitor factor t o be p r e s e n t in 14 of t h e
68 individuals tested (20%) (Table). N i n e of t h e m
(13%) showed inhibition at t h e range considered
positive (greater than 40% inhibition) a n d 5 a t t h e
equivocal range (inhibition 25 t o 40%). Five of t h e 7
family m e m b e r s with neurological abnormalities
were f o u n d to excrete the inhibitor. T h i s incidence of
inhibitor factor i n neurologically affected individuals
was significantly higher than that i n asymptomatic
family m e m b e r s (p < 0.001). The 20% overall rate of
positive and equivocal inhibition i n t h e investigated
population was significantly higher (p < 0.05) than
t h e r e p o r t e d incidence [I71 i n healthy adult controls
(45%)or patients with various neurological disorders
(6.7%).
306 Annals of Neurology
Total
No 4 April 1980
52
2
54
Case Histories
Propositus (Patient VI-39)*
This man, 2 1 years old at death, was born after a full-term
pregnancy complicated by hyperemesis gravidarum.
Neonatal and early development were considered normal.
A single episode of seizures occurred at age 7 months during an attack of gastroenteritis. During his early school
years he insidiously developed strabismus, impaired visual
acuity, a broad-based gait, and mild mental retardation.
Despite these symptoms he lived an active life until 20
years of age, when, following a respiratory infection
(pneumonitis), a complex of symptoms reminiscent of Ondine's curse syndrome [22] appeared. This was associated
with increasing gait disturbances, slurred speech, tremor,
and deteriorating vision. O n e year after the appearance of
the respiratory difficulties, an acute episode of stupor culminated in severe brainstem dysfunction and death within
three weeks. Postmortem examination revealed the characteristic pathological changes of SNE [ 2 5 ] .
Investigation of the family tree extended to seven generations and revealed parental consanguinity in this patient;
common maternal and paternal ancestors were traced to
the fifth preceding generation (1-3 and 1-4 in the Figure).
Living Family Members with Neurological
Abnormalities and Presence of the Inhibitor Factor
PATIENT VII-9. This 12-year-old girl had been born after
a full-term pregnancy during which the mother suffered
from severe bouts of vomiting. Her development was normal until 6Y2 months (held head at 2Y2 months and sat at 6
months), when retrogression followed an upper respiratory
tract infection associated with anorexia, vomiting, and
weight loss. She became less active and unable to hold her
head or sit unaided. Four months later she had another
exacerbation associated with anorexia, vomiting, and
diarrhea. This resulted in apathy, muscular hypotonia,
feeding difficulties, and marked body wasting. Generalized
tonic convulsions began at 1 1 months. Shortly after the
onset of her seizure disorder, bilateral ptosis, nystagmus,
and right hemiparesis with foot drop were noted. Neurological evaluation at that time was inconclusive. By 3 years
of age anorexia and body wasting had improved spontaneously, and ocular signs and right hemiparesis began to clear.
Though developmental regression ceased by this age, se-
*Pedigree number (see the Figure)
Vol 7
Negative
( s2 5 % )
vere mental and motor retardation remained. She was not
able to hold her head again until 3 years of age, and she did
not walk until 6 years.
Current neurological evaluation revealed a severely retarded girl who was unable to speak comprehensibly. Her
height was 130 cm, weight 26 kg, and head circumference
4 9 cm (microcephalic). She exhibited hypermetric movements of the upper extremities and periods of continuous
stereotyped behavior and hyperventilation. There was a
small central cataract in the right eye and sharply demarcated pale discs bilaterally. She walked with a broad-based
gait, dragging the right foot, which was externally rotated.
The stretch muscle reflexes were hyperactive with abnormally sustained flexor plantar responses bilaterally. H e r
balance was poor, and ataxia with intention tremor was obvious during her attempts to reach various offered objects.
Laboratory investigations including blood counts and
chemistries, urine amino acids, bone marrow aspiration,
and karyotype were negative. An electroencephalogram
showed diffuse multifocal spikes and spike and wave complexes. H e r fasting blood pyruvate level was 0.6 mgldl
(normal, 0.4 to 0.9 mgldl), and 0.9 m d d l two hours following glucose administration, 1.75 g m per kilogram of
body weight (normal, 0.6 to 1.2 mg/dl). Urine assay for
inhibitor factor showed 40% inhibition. Parental consanguinity was present (see the Figure).
PATIENT VII-14. This 8-year-old boy had been born by
cesarian section for breech position after a full-term pregnancy complicated by hyperemesis gravidarum. Early infantile development appeared normal: he smiled at 6 weeks
and followed visual stimuli at 2 months. At 4 months of age
the parents noted frequent rolling eye movements and observed that the infant no longer followed visual stimuli.
Neurological examination revealed upbeat nystagmus and
dysconjugate ocular movements as well as generalized
hyperreflexia with extensor plantar responses bilaterally.
Funduscopy showed questionable optic atrophy, absent
fovea reflex, and a red spot on the macula in both eyes.
Electroencephalography and skull roentgenograms with
views of the optic foramina were normal.
The visual impairment became more obvious in the ensuing months and years, and convergence strabismus and
coarse vertical nystagmoid eye movements appeared.
Funduscopic examination at 4 years of age revealed optic
atrophy and grayish fundi.
Current neurological evaluation showed a thin boy
(weight, 20 kg) with short stature (height, 120 cm) and a
hypotrophic muscular system. He appeared blind, with visual acuity limited to finger counting. He had synophrys of
the eyebrows and sunken, deep-set eyes. The pupils were
round and regular with delayed response to light and alternating anisocoria. Esotropia and pendular horizontal, vertical, and rotatory nystagmoid eye movements were observed. Funduscopy disclosed a gray retina, absent fovea
reflex, and optic atrophy. The fasting blood pyruvate level
was within normal limits (0.5 mgldl), and no rise occurred
following glucose intake (1,7 5 g d k g body weight). Other
laboratory studies, including computerized axial tomograms of the head and the orbits, were unremarkable. In-
hibitor factor assay showed 26% inhibition. Consanguinity
was present in the parents (see the Figure).
VI-68. The birth history and early development
of this 11-year-old girl were not remarkable; however,
walking had been delayed (2Y2 years) due to severe
equinus deformities of the feet. No other difficulties were
reported.
Current neurological evaluation demonstrated normal
mental status for the patient’s age. There was divergent
strabismus with full ocular movements and normal visual
acuity. Generalized hyperreflexia was present with
equivocal plantar responses, a mild degree of gait and bilateral limb ataxia, and impaired diadochokinesia. Inhibitor
factor assay showed 68% inhibition. No parental consanguinity was found, though both parents are members of the
investigated pedigtee (see the Figure).
PATIENT
PATIENT V-37. The pediatric history of this 47-year-old
woman is unknown. She is considered to have had low intelligence since childhood; she was unable to continue
elementary school beyond the first grade. Intermittent
tremor involving only the head became noticeable at age
42.
Current neurological evaluation showed a mild to moderate degree of psychomotor retardation and emotional lability. Oscillating head tremor was present, but manual
immobilization of the head did not reveal underlying nystagmus. The remaining neurological evaluation was unremarkable. However an unusual musculoskeletal deformity,
consisting of symmetrically flexed middle fingers at the first
interphalangeal joint, had been present since birth. Inhibitor factor assay showed 41% inhibition.
PATIENT VI-40. A sibling of the propositus, this 17year-old boy is described as having striking facial
similarities to his brother. Birth history and early development were normal. At age 2 years he developed intermittent respiratory difficulties which ceased by age 10. He is
considered to be of borderline low intelligence, and though
he completed the sixth grade, he had to repeat one year of
school.
Current neurological evaluation revealed saccadic pursuit ocular movements and restricted facial expression.
There was increased muscle tone without tremor or cogwheeling rigidity, and fine finger movements were slow and
clumsy. Urine assay for inhibitor factor showed 60% inhibition. Parental consanguinity was present.
Living Family Members with Neurological
Abnormalities but Absence of the Inhibitor Factor
PATIENT V - 3 2 . This 50-year-old woman had been born by
natural delivery after a full-term pregnancy. Although her
early development was considered normal, walking and
speech acquisition were delayed (24 to 26 months). She
entered elementary school at 6% years of age and was able
to complete the first two years of schooling. At 8Y2 years
of age, following an acute illness characterized by vomiting,
diarrhea, and stomatitis, psychomotor regression occurred.
Since then she has remained mentally retarded, with motor
Plaitakis et al: Chronic Leigh Disease
307
slowness and walking difficulties leading to repeated falls.
Secondary sex characteristics and menstrual cycle developed normally.
Current neurological evaluation revealed a thin woman
with short stature, myxedematous skin, and a moderate degree of psychomotor retardation. Speech was slurred and
slow. Muscle hypotonia, pendular reflexes, and impairment
of fine coordination were present. H e r gait was slow,
slightly broad based, and unsteady, and she was unable to
perform tandem walking.
PATIENT VI-73. The product of afull-term pregnancy and
uncomplicated natural delivery, this 1 I-year-old girl was
noted to have delayed acquisition of motor skills and language (walked at 20 months, acquired sentence speech at
4y2 years). She experienced a single tonic seizure at 4 years
of age. Neurological evaluation when she was 5 years old
showed a moderate degree of psychomotor retardation of
unknown cause.
Current neurological evaluation disclosed a moderate
degree of psychomotor retardation, emotional liability, and
divergent strabismus with full ocular movements and normal visual acuity.
Family Members Without Neurological Abnormalities
but With the Inhibitor Factor
Nine family members had positive or equivocal urine tests
but normal neurological examinations (see the Figure and
Table). Only 1 of these had a past history of neurological
difficulties. This individual, a 7-year-old boy (VI-44), had
experienced a single convulsion at 7 months of age during
the course of measles. He remained well thereafter until
age 6 years, when he rather suddenly developed dizziness,
unsteadiness, generalized weakness, and loss of appetite.
Symptoms subsided after a few weeks, and the patient has
had no further difficulties.
Deceased Family Members
with Neurological Abnormalities
Of the 49 deceased family members, 8 other than the
propositus had manifested neurological abnormalities. Although details of clinical neurological evaluation could not
be obtained on any of these individuals, the available historical data on 5 suggest that they suffered neurological
illnesses at least compatible with SNE. Among these 5 persons, 2 deaths occurred in siblings (V-38, V-39), at 8
months of age, who a few weeks prior to death developed
unexplained feeding difficulties and a peculiar persistent
cry. O n e death occurred in a 9-year-old boy (VI-62) who
for six months suffered intermittent episodes of vomiting
and respiratory difficulties, then died following acute development of a comatose state. Another occurred during a
generalized convulsion in an 1 I-year-old girl (VI-27) with
severe psychomotor retardation and marked spasticity. T h e
fifth death was that of a 22-year-old woman (IV-20) with a
complex of symptoms similar to that of the propositus.
Three family members died of neurological illnesses
probably not related to Leigh disease. Two (V-2, V-21)
were described as having mongolism, and the third, a 47year-old woman (V-24), died after a three-week neurolog-
308 Annals of Neurology
Vol 7
No 4
April 1980
ical illness attributed to tetanus infection. Among the deceased family members was a brother of the propositus
(VI-42) who died at 2 years of age after acute respiratory
symptoms. Though a neurological origin for his death cannot be excluded, he lacked antecedent neurological manifestations.
Discussion
Leigh disease in adults so far has been identified only
at postmortem examination [23]. Since mild forms of
the disease may not be recognized clinically and
therefore may not come to autopsy, the disorder
could be more widespread than has previously been
evident [6, 171.
The present study investigated a small, inbred
population uncovered when an adult patient was
found at autopsy to have died of Leigh disease. The
clinical characteristics of the family members with
neurological abnormalities may be summarized as
follows: (1) variable clinical expression, with mental
retardation present more commonly than other neurological manifestations; ( 2 ) marked variability in the
degree of involvement, ranging from subtle clinical
deficits to severe incapacitation; ( 3 ) appearance of
neurological manifestations in infancy or early childhood after initially normal development; (4) either
insidious or abrupt onset, sometimes associated with
metabolic stress; and ( 5 ) chronic remitting course in
most cases, with evidence of a static encephalopathy
or even recovery.
Our study appears to confirm that the investigated
population is at high risk for development of SNE,
since the incidence of the inhibitor factor (14 out of
68, o r 20%) was significantly higher than in a control
population (4%)[19]. A strong correlation was found
between the incidence of inhibitor factor and the
presence of neurological abnormalities in family
members investigated. However, despite this correlation, only 3 of the 7 neurologically affected family
members showed inhibition to a degree considered
unequivocally abnormal (340%).Two showed inhibition in the equivocal range ( 2 5 to 40%),while 2 individuals lacked the inhibitor factor by urine assay.
The TDP-ATP phosphoryltransferase inhibitor
factor has proved useful in the diagnosis of SNE
during life [ 3 , 4 , 17-19] and has correlated with
pathological evidence of the disease. False positive
and false negative results have been reported [17191. Because the inhibitor factor can be found in
asymptomatic relatives of patients with SNE, in
whom it presumably represents the heterozygous
state of the disease [ 1 5 ] , and since the degree of
phosphoryltransferase inhibition does not correlate
with the activity of the illness, this test cannot discriminate between a healthy carrier and an affected
patient [15, 171.
Based on these considerations, only the presence
of a neurological disorder compatible with SNE in a
family member found to excrete the inhibitor factor
would reasonably imply that the individual is affected
by SNE. Of the 5 family members with neurological
abnormalities and presence of the inhibitor factor,
the individual most severely involved (VII-7) presented with symptoms and signs most commonly encountered in infantile and childhood cases of SNE,
i.e., psychomotor retardation, feeding difficulties,
hypotonia, weakness, and episodes of vomitingfindings described in about 50 to 70% of patients in
whom symptoms begin during infancy [ 14, 171. Corticospinal tract signs, oculomotor deficits, optic atrophy, movement disorders, and seizures-also observed in this g i r l - a r e reported in about 30 to 55%
of patients with SNE [14, 171. Microcephaly, which
she also has, was encountered in 6 out of a series of
86 patients pathologically proved to have SNE and
has been considered suggestive of early nervous system involvement [ 171. Exacerbations of the disease,
usually associated with fever as noted in this same
girl, have occurred in 50 to 60% of cases of SNE
[ 171. Pincus has suggested that acute exacerbations in
a neurologically affected child should raise the possibility of SNE [ 171. Spontaneous remissions, usually
of short duration, have been encountered in 25% of
childhood cases. Remissions of longer duration (up
to 26 years) have occurred in juvenile and adult patients [23].
In the present study, severe neuroretinal and
oculomotor system involvement occurred in Patient
VII-14, an 8-year-old boy. This history, though unusual, is not exceptional in SNE. Monpetit et a1 [14]
in 177 1 reported their study of a family afflicted with
SNE in which optic atrophy with blindness was the
presenting symptom for the affected family members
well before other symptoms developed. Pathological
evidence of retinal degeneration with loss of ganglion
cells and thinning of nerve fiber layers has been described in SNE [7, l l ] . A variety of oculomotor disturbances similar to those described in Patient
VII-14 has also been observed in cases of SNE.
Examples include strabismus, various types of nystagmus, rolling, dissociated, or bizarre ocular movements, and pupillary changes [ l , 2, 7, 9, 11, 13, 14,
17, 181.
The mild degree of neurological involvement in
the other 3 family members with positive inhibitor
factor (V-37, VI-40, and VI-68) may reflect a premorbid state of the illness similar to that described in
a number of adult patients with SNE [6, 23-251, including the propositus. Such deficits may characterize
a state of reduced expression of the disease. The absence of inhibitor factor in the remaining 2 neurologically afflicted members does not exclude the pres-
ence of SNE since a 20% false negative rate has been
encountered in a recent series of pathologically documented cases [2O].
Of the 8 neurologically afflicted deceased family
members, clinical histories in 5 suggest a course
compatible with SNE. Involvement of the respiratory
center might have been the cause of death in the 9year-old boy (VI-62) who manifested intermittent
breathing difficulties and died of acutely developing
coma. Episodic vomiting and respiratory disturbances
such as hyperventilation, irregular respirations, and
apneic spells with stupor and coma resulting in death
are not uncommonly encountered in Leigh disease
[14, 17, 24, 251. Feeding difficulties, usually related
to bulbar palsy, and abnormal cry (weak or peculiar),
as observed in 2 deceased family members (V-38 and
V-39), are among the most common neurological
presentations of SNE manifested during infancy [5,
14, 17, 211.
Investigation of the family tree for seven generations not unexpectedly revealed parental consanguinity in several family members in this small population. Identification of parental consanguinity in the
propositus as well as in other family members with
neurological abnormalities and presence of the inhibitor factor suggests that Leigh disease in adults is
transmitted as an autosomal recessive trait. This conclusion is supported by the observations that both
males and females are affected and no vertical transmission of the trait was found; all parents of neurologically affected individuals were asymptomatic.
Further analysis of the investigated pedigree suggests
that the mutant gene was probably present in one of
the common ancestors (1-3 or 1-4) and was passed to
his or her descendants, with neurological illness of
variable expressivity appearing primarily in the offspring of consanguinous parents (VI-39, VI-40,
VII-7, and VII-14).
Previous genetic studies on SNE, though based
solely upon data from affected siblings, also suggest
that the disease in children is inherited in an autosomal recessive manner [14, 171. The illness has
not been shown to occur in successive generations;
however, two recent reports have described Leigh
disease in children of families afflicted by vertically
transmitted spinocerebellar syndromes [8, 101.
Leigh disease is remarkable as a genetic disorder
not only because of the extensive variability of its
clinical presentation, but also because of its often intermittent progression. The factors influencing the
expression and natural history of this neurological
disorder cannot presently be identified. However, in
some neurologically afflicted patients, inhibitor factor has been suppressed by high-dose thiamine therapy with concomitant clinical improvement [ 16-18],
and the suggestion has been made that daily nutriPlaitakis et al: Chronic Leigh Disease
303
tional intake of thiamine can suppress the inhibitor in
susceptible individuals [ 161.
In the present study and in previous reports [16,
171, onset or worsening of symptoms frequently
followed infection, diarrhea, and vomiting. Hyperemesis gravidarum complicated pregnancy in 3
neurologically affected family members in our study.
It is conceivable that during such stressful episodes,
associated with decreased vitamin supply, thiamine
metabolism is further compromised and an induced
relative deficiency leads t o nervous system damage.
We postulate that the variation in expression, variable degree of severity, and saltatory progression of
SNE in different individuals may be influenced by
exogenous factors aggravating the metabolic defect
underlying the disease.
Since the urine assay for TDP-ATP phosphoryltransferase inhibitor factor was performed as a
screening test in a large number of individuals from a
high-risk population, the question can be raised
whether the presence of positive and equivocal inhibition in asymptomatic family members, especially
young children, predicts the development of SNE in
some of these individuals. A long-term follow-up of
the investigated family will be necessary to answer
this question.
Supported by NINCDS Grant NS-11631, Grant JTO1-NS05062-2 1. and Fellowship Award NS-05843 from the National Institutes of Health and by Grant NS-08661 from the US Public
Health Service.
Presented at the 102nd Annual Meeting of the American Neurological Association, Chicago, IL, April 20, 1977.
The authors wish to thank Dr Kurt Hirschhorn for his thorough
review of the manuscript and constructive comments. The technical assistance of Ms Katalin Piros in the inhibitor assays is gratefully acknowledged.
References
1. Borit A: Leigh’s necrotizing encephalomyelopathy. Arch
Ophthalmol 85:438-442, 1971
2. Clayton BE, Dobbs RH, Patrick AD: Leigh’s subacute necrotizing encephalomyelopathy: clinical and biochemical study,
with special reference to therapy with lipoate. Arch Dis Child
42:476-478, 1967
3. Cooper JR, Itokawa Y, Pincus JH: Thiamine triphosphate
deficiency in subacute necrotizing encephalomyelopathy. Science 164:72-73, 1969
4. Cooper JR, Pincus JH, Itokawa Y , et al: Experience with
thiamine phosphoryltransferase inhibition in subacute necrotizing encephalomyelopathy. N Engl J Med 283:793-795,
1970
5. Davis RA, Wolf A: Infantile beriberi associated with Wernicke’s encephalopathy. Pediatrics 2 1:409-420, 1958
310 Annals of Neurology
Vol 7 No 4
April 1980
6. Feigin I, Goebel H H : “Infantile” subacute necrotizing encephalomyelopathy in adults. Neurology (Minneap) 19:749759, 1969
7. Feigin I, Wolf A: A disease in infants resembling chronic
Wernicke’s encephalopathy. J Pediatr 45:243-263, 1054
8. Greenwood RS, DeVivo DC, Nelson JS, et al: An autosomal
dominant form of necrotizing encephalomyelopathy resembling a spinocerebellar degeneration. Trans Am Neurol Assoc
100:47-51, 1975
9. Grover WD, Green WR, Pileggi AJ: Ocular findings in subacute necrotizing encephalomyelitis. Am J Ophthalmol
70:599-603, 1970
10. Guggenheim MA, Stumpf DA: Familial metabolic disease
with clinicopathological findings of both Leigh’s disease and
adult type spinocerebellar degeneration. Ann Neurol
2:264-265, 1977
11. Howard RO, Alber DM: Ocular manifestations of subacute
necrotizing encephalomyelopathy (Leigh’s disease). Am J
Ophthalmol 74:386-393, 1972
12. Leigh D: Subacute necrotizing encephalomyelopathy in an
infant. J Neurol Neurosurg Psychiatry 14:216-221, 1951
13. Martin JJ: Sur la delimitation clinicopathologique de I’encephalopathie de Gayet-Wernicke et de la forme adulte de
I’encephalopathie de Leigh. Acta Neurol Belg 72:347-354,
1972
14. Monpetit VJA, Anderman F, Carpenter S, et al: Subacute necrotizing encephalomyelopathy. A review and a study of two
families. Brain 94:l-30, 1971
15. Murphy JV: Subacute necrotizing encephalomyelopathy
(Leigh‘s disease): detection of the heterozygous carrier state.
Pediatrics 51:710-715, 1973
16. Murphy JV: Leigh’s disease. Biochemical characteristics in the
inhibitor. Arch Neurol 31:220-227, 1974
17. Pincus JH: Subacute necrotizing encephalomyelopathy
(Leigh’s disease): a consideration of clinical features and etiology. Dev Med Child Neurol 14:87-101, 1972
18. Pincus JH, Cooper JR, Itokawa Y, et al: Subacute necrotizing
encephalomyelopathy. Effects of thiamine and thiamine propyl disulfide. Arch Neurol 24511-517, 1971
19. Pincus JH, Cooper HR, Piros K, et al: Specificity of the urine
inhibitor test for Leigh‘s disease. Neurology (Minneap)
24:885-890, 1974
20. Pincus J H , Solitare GB, Cooper JR: Thiamine triphosphate
levels and histopathology. Correlation in Leigh’s disease. Arch
Neurol 33:759-763, 1976
2 1. Richter RB: Infantile subacute necrotizing encephalopathy
(Leigh’s disease): its relationship to Wernicke’s encephalopathy. Neurology (Minneap) 18:1125-1132, 1968
22. Seriff NS: Alveolar hypoventilation with normal lungs: the
syndrome of primary or central alveolar hypoventilation. Ann
N Y Acad Sci 121:691-705, 1965
23. Sipe JC: Leigh’s syndrome: the adult form of subacute necrotizing encephalomyelopathy with predilection for the brainstem. Neurology (Minneap) 23:1030-1038, 1073
24. Solheid C, Stoupel N, Martin JJ: La forme adulte a evolution
chronique de I’encephalopathie necrosante de Leigh. Sa situation vis-a-vis des formes infanto-juveniles. Acta Neurol Belg
71:282-295, 1971
25. Whetsell WO, Plaitakis A: Leigh’s disease i n an adult with evidence of “inhibitor factor” in family members. Ann Neurol
3:519-524, 1978
Документ
Категория
Без категории
Просмотров
0
Размер файла
709 Кб
Теги
stud, disease, genetics, leigh, biochemical, chronic
1/--страниц
Пожаловаться на содержимое документа