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Heterogeneous findings in four cases of cerebellar ataxia associated with hypogonadism (Holmes' type ataxia)
Cli~zicuINerrrolu~~~ md i~~zir~j.sur~f‘~~; 95 ( 1993) 23 -28 0 1993 Elsevier Science Publishers R.V. All rights reserved 0303-~~67/93/$06.00
23
CLINEU 00226
Heterogeneous
findings in four cases of cerebellar ataxia associated with hypogonadis~ (Holmes type ataxia)
G. De Michele”, A. Filla”, S. Strianoa, M. Rimoldib and G. Campan~lla~ “Department of Neurology, Second School oJ’Medicine, Universitli Federico Ii, Nrrples, Itulll und bLuhorator_y of’ Biochemistry Genetics, Istit~it~ ~e~r~~l~~g~c~ ‘C. Bestu’, ,~~illln,It&
und
(Received 21 April, 1992) (Revised version received12 June, 1992) (Accepted 24 September. 1992) Kq) words:
Cerebellar ataxia; Hypogonadism;
Holmes’ type ataxia
Summary
We report four sporadic cases of cerebellar ataxia associated with hypogonadism. All patients were female. The neurological symptoms appeared in the first three decades. Apart from ataxia, the most frequent features were nystagmus, dysarthria, mental impairment, brisk tendon reflexes, skeletal deformities, peripheral neuropathy, and tremor. Neuroima~ing studies showed constant cerebellar atrophy, in some instances associated with involvement of either grey or white cerebral matter. Neurophysiological studies demonstrated an axonal neuropathy. Endocrine evaluation showed heterogeneity of the hypogonadism. which was hypogonadotrophic in one patient and hypergonadotrophic in the other three. One patient had partial deficiency of muscle cytochrome r oxidase. The syndrome appears to be a heterogeneous multisystem disorder and in some cases a mitochondrial metabolism deficiency could be suspected.
introduction
The association of cerebellar ataxia and hypogonadism (AH) was first described in four sibs by Holmes [I], who reported the autopsy findings of one case showing degeneration of the cerebellum and inferior olives. In the original Holmes’ description, ataxia was inherited in an autosomal recessive fashion and associated with hypogonadism. Since then, cases of cerebellar ataxia with a dominant inheritance and without hypogonadism have been labeled as ‘Holmes’ type inherited ataxia’ only because cerebella-olivary degeneration was found at autopsy [2]. Harding [3] reviewed the topic and found about 20 reported cases of AH, either sporadic or autosomal reCorrespondmcc to: Dr. Ciuseppc De Michele, C’linica Neurologica, Seconda Facolth di Medic& via Pansini 5, 80131 Napoli. Italy. Tel.: 8 117462597:Fax: 8 11546154I.
cessive. The hypogolladism was hypogonadotrophi~ in most cases, but. since cases with increased levels of gonadotrophins have also been reported. an endocrine heterogeneity exists. We report the clinical and laboratory findings in 4 sporadic cases of AH.
Case reports
Clinical features of the patients are listed in Table 1. All patients had a negative family history.
The clinical and pathological findings of this case have already been reported [4]. The patient reported primary amenorrhea treated with oestrogens and progesterone. When she was 30, a general examination showed normal breast development. scanty axillary and pubic hair. En-
24 docrine
data, shown in Table 2, demonstrated
dotrophins
which did not increase
and low basal estradiol
which increased
ml) after administration
of clomiphene.
crine
TSH
assays,
were normal. more marked
including
A CT scan
ries,
of the lung, hypoplastic
Purkinje exclude
atrophy
of the pons.
There
atrophy
showed
uterus,
mutinous
atrophic
was neuronal
nucleus
ataxia,
cerebellar
the patient
slight
loss in the
and inferior
olives. findings
degeneration
had primary
ova-
and
of the disease and the pathological
a paraneoplastic
CLl,W2 Besides
after TRH,
cerebellar
of the cerebellum
cell layer, dentate
The duration
(55 pg/
in the vermis (Fig. 1). At the age of 35 she
moderate
shrinkage
slightly
The other endo-
and prolactin revealed
died after a brief illness. The autopsy carcinoma
low gona-
after 5 days LHRH
[4].
amenorrhea
TABLE 1 CLINICAL
FEATURES ____.
Case
I
2
3
4
Consanguinity Sex Age at onset Age at last examination Gait ataxia Nystagmus Abnormal eye movements’ Dysarthria Dysmetria Lower limb tendon reflexes distal wasting distal weakness decreased vibration sense Plantar response Mental impairment Tremor* Urinary incontinence Skeletal derformities” Associated features
F 18*
F <30
_
+
F 2
F
34 + ++
56 +++ +
30 + +
14 + +
+ + +
+ +
+ ++ ++
+ + -
brisk -
brisk + +
brisk
weak -
_
+
Fig. I. CT scan of case 1 showing atrophy of the vermis and marked
13*
were increased, Other endocrine
+ normal normal fi+ + + _ + dysphagia
normal ++ + + -
+ absent ++ + ptosis, hypoacusia
+ to +++ indicates presence and relative severity of features; indicates absence of features. *Aways clumsy. #Abnormal eye movements consisted in dysmetric saccades and jerky smooth pursuit in cases 1,3,4 and ocular flutter in case 3. -Head tremor in case 1, intention tremor in case 2. “Claw toes in case 1, pes cavus in case 3. scoliosis in case 4.
deterioration,
delusions
and agita-
estradiol and progesterone were low. data were normal. EEG showed diffuse
slowing. EMG of biceps brachialis and tibialis showed neurogenic changes. Motor conduction
anterior velocity
TABLE 2 ENDOCRINE
_
mental
tion. General examination showed normal secondary sexual characteristics, but scanty axillary hair. Endocrine findings are shown in Table 2. Gonadotrophins
DATA
Case
1
Estradiol (20-240 pg/ml) Progesterone (0.3-25 &ml) Testosterone (0.3-I .2 ng/ml) FSH (5-30 mu/ml) LH (5-60 mU/ml) Total T, (0.61.9 @ml) Total T, (45-l 10 @ml) TSH (0.54 PUlml) Cortisol (50-250 @ml) ACTH (lo-130 pg/rnI)
13.0 -
2
14.0 0.1 0.9 1.1 0.5 197.3 1.5 220.0 1.0 1.0 65 71 0.6 1.6 91 39 25 18
3
3
9.2 0.3 0.2 175.7 122.9 1.3 80 2.1 102 12
20.0 0.8 0.6 180.0 86.0 1.4 93 2.7 247 12
Normal ranges are show in brackets. For sexual hormones it comprises follicular, ovulatory and luteinic phases. In postmenopausal age (case 2) normal range is 50-100 mU/ml for both FSH and LH. Cortisol and ACTH levels refer to 8 a.m.
25
of tl te rnedian nerve wa s slightly slowed and the motor evok :ed potential amplil ude markedly decreased. VEPs shov 4ed increased latent :y and BAEPs were normal. CT scan Wa LSnot performed because of poor cooperation. Cast 13
In thjis patient menarc :he occurred at age 12, but men-
struation was subsequently irregular ant1 disappc:ared at age 16. She was treated with oestrogen s and pr ogesterone. An endoscopic examination showc:d a hyp oplastic uterus and atrophic ovaries, which at biopsy showed thickening of albuginea and absence of ’ follicles . Breast and body hair development was normal. Endocr ine data reported in Table 2 showed increased gonadot rophins
Fig. 2. (:T scan of case 3 showing (a) hypodense periventricular white matter, more evident at level of front al horns, and (b) enlargement of the IV ventricle and cerebellar cistern.
26 and decreased estradiol and progesterone. At age 30, behaviour and cognitive dysfunction appeared: poor memory with confabulation, lack of initiative. apathy, sphincteric incontinence, disinhibition, poor self-care. This was progressive and the patient, who had been a teacher, became totally dependent. The EEG revealed moderate diffuse slowing; VEPs were normal. CT scan and MRI showed abnormal periventricular white matter and cerebellar atrophy (Figs. 2-3). EMG of the biceps brachialis and tibialis anterior was normal. Conduction studies showed slight slowing of sensory velocity in the median nerve. In the tibialis posterior nerve, distal sensory velocity was slightly slowed and distal motor latency increased. Karyotype was 46, XX. Arylsulphatase A and hexosaminidases A and B were normal. Biopsy of quadriceps femoris revealed no specific abnormalities, but variability of the fiber size, presence of vacuoles in the smallest fibers, diffuse decreased reactivity of cytochrome oxidase, and slight predominance of type 1 fibers were observed. The biochemical assay of the muscle and fibroblast mitochondrial enzyme showed a partial deficiency of muscle cytochrome c oxidase (Table 3). The patient became bedridden and died at age 33. Case 4 The parents of this 17-year-old girl were first cousins.
Fig. 3. T,-weighted MRI of case 3 showing increased signal of the periventricular white matter more evident in the frontal region.
I-ABLE 3 MITOCHONDRIAL ENZYME ACTIVITIES -
Muscle
._ _. _ _. _
NADH:ferricyanide
IN (‘ASI. ; f-ibroblasth
reductase
14% 3742 1450 ? 365 ‘890 t 53X (870 3000) (2300 -1000) NADH:cytochrome c reductase 64.7 32 (total activity) 61 f I6 153 L!J7 (30 90) (70 -. -‘5(l) _1-l < i I Succinate dehydrogenase -_._ I’)& 7 XT 3 (7 2X) (3 14) 17.5 5.6 Succinate:cytochrome c reductase 13&i 5.rI (5 1) (3 0) Cytochrome c oxidase 13.9 37.3 68 _+20 25 z!I IO (25 100) (10 44) Cyt. c oxidase succ:cyt. c reductase 0.8 6.7 4.9 -..
-
(7.7 ..-
I? 1.1 7) _
._
4.3
t
I .o
(3 6) __. ._ ._
Enzyme activities were determined in crude extracts, according to Sottocasa et al. [15]. Values are expressed as nmol/min/mg non collagen protein. Normal means f. SD and ranges (in brackets) are shown.
At age 4 she had had a grand ma1 seizure. The patient had never menstruated and general examination showed a breast development in phase 34 and only initial development of pubic and axillary hair. Table 2 shows endocrine evaluation with increased gonadotrophins and decreased estradiol. Ultrasonic examination of the pelvis showed ovaries of slightly reduced size and normal structure. ECG showed non-specific repolarization abnormalities. EEG was normal. Vestibular tests showed bilateral reduced reactivity and audiometry bilateral sensorineural hypoacusia. CT scan and MRI revealed enlargement of supratentorial and fourth ventricles and of the superior cerebellar cistern. The last finding is illustrated in Fig. 4. Neurophysiological study showed normal VEPs and SEPs, increased latency of BAEPs consistent with peripheral impairment, and slowed central motor conduction velocity. In the median and tibialis posterior nerves motor conduction study showed reduced velocity and decreased amplitude of the potential. whereas sensory conduction study was normal. EMG of the tibialis anterior and abductor digiti minimi showed marked neurogenic changes. Biceps brachialis muscle biopsy showed variability of the fiber size, a tendency to
27
Fig. 4. CT scan of case 4 showing enlargement of superior cerebellar cistern.
type grouping of type 1 fibers, and increased subsarcolemmal oxidative enzymatic activity.
Discussion
Since Holmes’ original description only a few patients with AH have been described. Harding’s personal series of 157 index cases of inherited ataxias included none with this syndrome [5}. Among our 182 index cases we found four patients (2.2%) from four different families. Family history was negative in all four and consanguinity was present in one case. Therefore, the disorder appears to be sporadic or inherited in an autosomal recessive fashion. In our patients the onset of the cerebellar features was in the first three decades; in 3 cases slight clumsiness had been reported since childhood. Apart from gait and limb ataxia, the most frequent features were: nystagmus. present in all our cases; mental impairment, abnormal eye movements, dysarthria, brisk tendon reflexes and skeletal deformities, present in 3 cases; tremor, urinary incontinence and peripheral neuropathy, present in 2 cases. Clinical signs of peripheral nerve involvement were: decreased vibration sense, distal weakness and wasting; tendon reflexes were always preserved. Laboratory investigation showed axonal degenerative
neuropathy in all three examined patients. Clinical features suggestive of peripheral neuropathy have sometimes been reported in AH 26-91, but our study offers the first neurophysiological demonstration. An axonal degenerative neuropathy is found in other hereditary ataxias, such as Friedreich’s disease, where it is constant and severe, and early onset cerebellar ataxia with retained tendon reflexes, where it is present in about half of the patients [lo]. Neuroimaging studies performed in three patients always showed mild cerebellar atrophy, mostly of the vermis. Abnormalities of the white matter, prevalent in the frontal region were found in patient No. 3 who was severely demented. Loss of myelinated fibers and astrocyte proliferation in the white matter of hemispheres and thalamus were present at autopsy in one patient who was also demented [ll]. Enlargement of the supratentnrial ventricles was present in case No. 4. The endocrine study of our patients showed decreased gonadotrophin levels in case 1. The negative LHRH test even after a 5-day administration suggests the absence of pituitary response, whereas the response to clomiphene showed slight residual function. The other 3 patients had increased gonadotrophin levels with increased response to LHRH and decreased levels of estradiol and progesterone. These findings are consistent with a primary hypogonadism. However, the post-menopausal age of patient No. 2 should be considered in interpreting these results. In one of our cases a partial deficiency of muscle cytochrome L’oxidase was found. Mitochondrial myopathies are often associated with endocri~lopathy (diabetes. hypoparathyroidism, hypogonadism) [ 121. In particular they have been seen in association with either hypothalamic infertility [13] or primary hypogonadism 1141.On the other hand, a mito~hondrial encephalomyop~~thy may account for cerebellar ataxia and also for some reported accessory features, such as dementia, retinal degeneration, epilepsy, choreoatethosis, ophthalmoplcgia, and deafness. In conclusion the occurrence of AH is probably underestimated and we suggest a careful evaluation of gonadic function in ataxic patients. Variability of onset age, of neurological picture, and of endocrine findings favours the hypothesis that AH is a heterogeneous syndrome. A thorough laboratory investigation, including neurophysiological and neuroradiological studies, may reveal a multisystemic nervous system involvement. We suggest that mitochondrial metabolism impairment may be a likely aetiology in some cases.
.4cknowledgement
Supported Ministry
by grants
from CNR
(No. 91.04180)
and
9
of Education.
References
Holmes. G. (1907) A form of familial degeneration of the cerebellum. Brain 30: 466489. Greenfield. J.G. (1954) The Spino-cerebellar Degenerations. Blackwell, Oxford. Harding. A.E. (1984) The Inherited Ataxias and Related Disorders. Churchill Livingstone, Edinburgh, pp. lO9- 114. De Michele, G.. Filla, A.. D’Armiento, F.P. et al. (1990) Cerebellar ataxia and hypogonadism: a ChnicopathoJogical report. Clin. Neurol. Neurosurg., 92: 67 -70. Harding, A.E. (1983) Classification of the hereditary ataxias and paraplegias. Lancet. i: I I5 I I 155. Boitelle. G.. Delteil, P., Noel, P. and Foncin. J.F. (1956) Degeneration spinodrebelleuse. type Friedreich. avec infantilisme hypogonadotrophique et senilite precoce. Ann. Med. Psychol.. 114: 839-844. Vignalou, J.. Berthaux, P.. Goygou. C.. Colas-Belcoeur. J.F.. Lemarchalle. A. and Hamel, A. (1959) Hypogonadisme hypogonadotrophique associe a une maladie de Friedreich. Ann. Endocrinol. (Paris). 20: 172.- 177. Bernard-Weil. E. and Endtz. L.J. (1962) Sur un cas familial
IO
II I2 13
I4
I5
de degeneration spinodrebelleuse avec cunuchoidisme hypogonadotrophique. Presse Med.. 70: 524.-526. Berciano. J.. Amado. J.A., Freijane. J.. Rebollo. M. and Vaquero. A. (1982) Familial cerebellar ataxia and hypogonadotropic hypogonadism: evidence for hypothalamrc LHRH deficiency. J. Neurol. Neurosurg. Psychiat.. 45: 747 751. Filla. A.: De Michele, G.. Cavalcanti, F. et al. (19!90)Clinical and genetic heterogeneity in early onset cerebellar ataxia with retained tendon reflexes. J. Neurol. Neurosurg. Psychiat., 53: 667-670. Matthews, W.B. and Rundle, A.T. (1964) Familial cerebellar ataxia and hypogonadism. Brain, 87: 463468. Lombes, A.. Bonilla. E. and Di Mauro, S. (1989) Mitochondrial encephalomyopathies. Rev. Neurol., 145: 6671-6689. Fitzsimons. R.B.. Clifton-Bligh, P. and Wolfenden. W.H. ( I98 I ) Mitochondrial myopathy and lactic acidaemia with myoclonic epilepsy, ataxia and hypothalamic infertility: a variant of Ramsay-Hunt syndrome? J. Neurol. Neurosurg. Psychiat.. 44: 79 8.2. Julien. J., Vital, C.. Vallat. J.M., Roger, P.. Lunel, G. and Vallat. M. (1973) Myopathie oculairc avec hypogonadisme primairc. Anomalies mitochondrialcs en ultrastructur’c. Ke\. Ncurol.. IX 365 377. Sottocasa. G.L., Kuylcnstierna, 13.. Ernster. 1.. and Hergstrand. A. (1967) .4n electron-transport system associated with the outer membrane of liver mitochondria. A biochemical and morphological study. J. Cell Biol.. 32: 415 438.
23
CLINEU 00226
Heterogeneous
findings in four cases of cerebellar ataxia associated with hypogonadis~ (Holmes type ataxia)
G. De Michele”, A. Filla”, S. Strianoa, M. Rimoldib and G. Campan~lla~ “Department of Neurology, Second School oJ’Medicine, Universitli Federico Ii, Nrrples, Itulll und bLuhorator_y of’ Biochemistry Genetics, Istit~it~ ~e~r~~l~~g~c~ ‘C. Bestu’, ,~~illln,It&
und
(Received 21 April, 1992) (Revised version received12 June, 1992) (Accepted 24 September. 1992) Kq) words:
Cerebellar ataxia; Hypogonadism;
Holmes’ type ataxia
Summary
We report four sporadic cases of cerebellar ataxia associated with hypogonadism. All patients were female. The neurological symptoms appeared in the first three decades. Apart from ataxia, the most frequent features were nystagmus, dysarthria, mental impairment, brisk tendon reflexes, skeletal deformities, peripheral neuropathy, and tremor. Neuroima~ing studies showed constant cerebellar atrophy, in some instances associated with involvement of either grey or white cerebral matter. Neurophysiological studies demonstrated an axonal neuropathy. Endocrine evaluation showed heterogeneity of the hypogonadism. which was hypogonadotrophic in one patient and hypergonadotrophic in the other three. One patient had partial deficiency of muscle cytochrome r oxidase. The syndrome appears to be a heterogeneous multisystem disorder and in some cases a mitochondrial metabolism deficiency could be suspected.
introduction
The association of cerebellar ataxia and hypogonadism (AH) was first described in four sibs by Holmes [I], who reported the autopsy findings of one case showing degeneration of the cerebellum and inferior olives. In the original Holmes’ description, ataxia was inherited in an autosomal recessive fashion and associated with hypogonadism. Since then, cases of cerebellar ataxia with a dominant inheritance and without hypogonadism have been labeled as ‘Holmes’ type inherited ataxia’ only because cerebella-olivary degeneration was found at autopsy [2]. Harding [3] reviewed the topic and found about 20 reported cases of AH, either sporadic or autosomal reCorrespondmcc to: Dr. Ciuseppc De Michele, C’linica Neurologica, Seconda Facolth di Medic& via Pansini 5, 80131 Napoli. Italy. Tel.: 8 117462597:Fax: 8 11546154I.
cessive. The hypogolladism was hypogonadotrophi~ in most cases, but. since cases with increased levels of gonadotrophins have also been reported. an endocrine heterogeneity exists. We report the clinical and laboratory findings in 4 sporadic cases of AH.
Case reports
Clinical features of the patients are listed in Table 1. All patients had a negative family history.
The clinical and pathological findings of this case have already been reported [4]. The patient reported primary amenorrhea treated with oestrogens and progesterone. When she was 30, a general examination showed normal breast development. scanty axillary and pubic hair. En-
24 docrine
data, shown in Table 2, demonstrated
dotrophins
which did not increase
and low basal estradiol
which increased
ml) after administration
of clomiphene.
crine
TSH
assays,
were normal. more marked
including
A CT scan
ries,
of the lung, hypoplastic
Purkinje exclude
atrophy
of the pons.
There
atrophy
showed
uterus,
mutinous
atrophic
was neuronal
nucleus
ataxia,
cerebellar
the patient
slight
loss in the
and inferior
olives. findings
degeneration
had primary
ova-
and
of the disease and the pathological
a paraneoplastic
CLl,W2 Besides
after TRH,
cerebellar
of the cerebellum
cell layer, dentate
The duration
(55 pg/
in the vermis (Fig. 1). At the age of 35 she
moderate
shrinkage
slightly
The other endo-
and prolactin revealed
died after a brief illness. The autopsy carcinoma
low gona-
after 5 days LHRH
[4].
amenorrhea
TABLE 1 CLINICAL
FEATURES ____.
Case
I
2
3
4
Consanguinity Sex Age at onset Age at last examination Gait ataxia Nystagmus Abnormal eye movements’ Dysarthria Dysmetria Lower limb tendon reflexes distal wasting distal weakness decreased vibration sense Plantar response Mental impairment Tremor* Urinary incontinence Skeletal derformities” Associated features
F 18*
F <30
_
+
F 2
F
34 + ++
56 +++ +
30 + +
14 + +
+ + +
+ +
+ ++ ++
+ + -
brisk -
brisk + +
brisk
weak -
_
+
Fig. I. CT scan of case 1 showing atrophy of the vermis and marked
13*
were increased, Other endocrine
+ normal normal fi+ + + _ + dysphagia
normal ++ + + -
+ absent ++ + ptosis, hypoacusia
+ to +++ indicates presence and relative severity of features; indicates absence of features. *Aways clumsy. #Abnormal eye movements consisted in dysmetric saccades and jerky smooth pursuit in cases 1,3,4 and ocular flutter in case 3. -Head tremor in case 1, intention tremor in case 2. “Claw toes in case 1, pes cavus in case 3. scoliosis in case 4.
deterioration,
delusions
and agita-
estradiol and progesterone were low. data were normal. EEG showed diffuse
slowing. EMG of biceps brachialis and tibialis showed neurogenic changes. Motor conduction
anterior velocity
TABLE 2 ENDOCRINE
_
mental
tion. General examination showed normal secondary sexual characteristics, but scanty axillary hair. Endocrine findings are shown in Table 2. Gonadotrophins
DATA
Case
1
Estradiol (20-240 pg/ml) Progesterone (0.3-25 &ml) Testosterone (0.3-I .2 ng/ml) FSH (5-30 mu/ml) LH (5-60 mU/ml) Total T, (0.61.9 @ml) Total T, (45-l 10 @ml) TSH (0.54 PUlml) Cortisol (50-250 @ml) ACTH (lo-130 pg/rnI)
13.0 -
2
14.0 0.1 0.9 1.1 0.5 197.3 1.5 220.0 1.0 1.0 65 71 0.6 1.6 91 39 25 18
3
3
9.2 0.3 0.2 175.7 122.9 1.3 80 2.1 102 12
20.0 0.8 0.6 180.0 86.0 1.4 93 2.7 247 12
Normal ranges are show in brackets. For sexual hormones it comprises follicular, ovulatory and luteinic phases. In postmenopausal age (case 2) normal range is 50-100 mU/ml for both FSH and LH. Cortisol and ACTH levels refer to 8 a.m.
25
of tl te rnedian nerve wa s slightly slowed and the motor evok :ed potential amplil ude markedly decreased. VEPs shov 4ed increased latent :y and BAEPs were normal. CT scan Wa LSnot performed because of poor cooperation. Cast 13
In thjis patient menarc :he occurred at age 12, but men-
struation was subsequently irregular ant1 disappc:ared at age 16. She was treated with oestrogen s and pr ogesterone. An endoscopic examination showc:d a hyp oplastic uterus and atrophic ovaries, which at biopsy showed thickening of albuginea and absence of ’ follicles . Breast and body hair development was normal. Endocr ine data reported in Table 2 showed increased gonadot rophins
Fig. 2. (:T scan of case 3 showing (a) hypodense periventricular white matter, more evident at level of front al horns, and (b) enlargement of the IV ventricle and cerebellar cistern.
26 and decreased estradiol and progesterone. At age 30, behaviour and cognitive dysfunction appeared: poor memory with confabulation, lack of initiative. apathy, sphincteric incontinence, disinhibition, poor self-care. This was progressive and the patient, who had been a teacher, became totally dependent. The EEG revealed moderate diffuse slowing; VEPs were normal. CT scan and MRI showed abnormal periventricular white matter and cerebellar atrophy (Figs. 2-3). EMG of the biceps brachialis and tibialis anterior was normal. Conduction studies showed slight slowing of sensory velocity in the median nerve. In the tibialis posterior nerve, distal sensory velocity was slightly slowed and distal motor latency increased. Karyotype was 46, XX. Arylsulphatase A and hexosaminidases A and B were normal. Biopsy of quadriceps femoris revealed no specific abnormalities, but variability of the fiber size, presence of vacuoles in the smallest fibers, diffuse decreased reactivity of cytochrome oxidase, and slight predominance of type 1 fibers were observed. The biochemical assay of the muscle and fibroblast mitochondrial enzyme showed a partial deficiency of muscle cytochrome c oxidase (Table 3). The patient became bedridden and died at age 33. Case 4 The parents of this 17-year-old girl were first cousins.
Fig. 3. T,-weighted MRI of case 3 showing increased signal of the periventricular white matter more evident in the frontal region.
I-ABLE 3 MITOCHONDRIAL ENZYME ACTIVITIES -
Muscle
._ _. _ _. _
NADH:ferricyanide
IN (‘ASI. ; f-ibroblasth
reductase
14% 3742 1450 ? 365 ‘890 t 53X (870 3000) (2300 -1000) NADH:cytochrome c reductase 64.7 32 (total activity) 61 f I6 153 L!J7 (30 90) (70 -. -‘5(l) _1-l < i I Succinate dehydrogenase -_._ I’)& 7 XT 3 (7 2X) (3 14) 17.5 5.6 Succinate:cytochrome c reductase 13&i 5.rI (5 1) (3 0) Cytochrome c oxidase 13.9 37.3 68 _+20 25 z!I IO (25 100) (10 44) Cyt. c oxidase succ:cyt. c reductase 0.8 6.7 4.9 -..
-
(7.7 ..-
I? 1.1 7) _
._
4.3
t
I .o
(3 6) __. ._ ._
Enzyme activities were determined in crude extracts, according to Sottocasa et al. [15]. Values are expressed as nmol/min/mg non collagen protein. Normal means f. SD and ranges (in brackets) are shown.
At age 4 she had had a grand ma1 seizure. The patient had never menstruated and general examination showed a breast development in phase 34 and only initial development of pubic and axillary hair. Table 2 shows endocrine evaluation with increased gonadotrophins and decreased estradiol. Ultrasonic examination of the pelvis showed ovaries of slightly reduced size and normal structure. ECG showed non-specific repolarization abnormalities. EEG was normal. Vestibular tests showed bilateral reduced reactivity and audiometry bilateral sensorineural hypoacusia. CT scan and MRI revealed enlargement of supratentorial and fourth ventricles and of the superior cerebellar cistern. The last finding is illustrated in Fig. 4. Neurophysiological study showed normal VEPs and SEPs, increased latency of BAEPs consistent with peripheral impairment, and slowed central motor conduction velocity. In the median and tibialis posterior nerves motor conduction study showed reduced velocity and decreased amplitude of the potential. whereas sensory conduction study was normal. EMG of the tibialis anterior and abductor digiti minimi showed marked neurogenic changes. Biceps brachialis muscle biopsy showed variability of the fiber size, a tendency to
27
Fig. 4. CT scan of case 4 showing enlargement of superior cerebellar cistern.
type grouping of type 1 fibers, and increased subsarcolemmal oxidative enzymatic activity.
Discussion
Since Holmes’ original description only a few patients with AH have been described. Harding’s personal series of 157 index cases of inherited ataxias included none with this syndrome [5}. Among our 182 index cases we found four patients (2.2%) from four different families. Family history was negative in all four and consanguinity was present in one case. Therefore, the disorder appears to be sporadic or inherited in an autosomal recessive fashion. In our patients the onset of the cerebellar features was in the first three decades; in 3 cases slight clumsiness had been reported since childhood. Apart from gait and limb ataxia, the most frequent features were: nystagmus. present in all our cases; mental impairment, abnormal eye movements, dysarthria, brisk tendon reflexes and skeletal deformities, present in 3 cases; tremor, urinary incontinence and peripheral neuropathy, present in 2 cases. Clinical signs of peripheral nerve involvement were: decreased vibration sense, distal weakness and wasting; tendon reflexes were always preserved. Laboratory investigation showed axonal degenerative
neuropathy in all three examined patients. Clinical features suggestive of peripheral neuropathy have sometimes been reported in AH 26-91, but our study offers the first neurophysiological demonstration. An axonal degenerative neuropathy is found in other hereditary ataxias, such as Friedreich’s disease, where it is constant and severe, and early onset cerebellar ataxia with retained tendon reflexes, where it is present in about half of the patients [lo]. Neuroimaging studies performed in three patients always showed mild cerebellar atrophy, mostly of the vermis. Abnormalities of the white matter, prevalent in the frontal region were found in patient No. 3 who was severely demented. Loss of myelinated fibers and astrocyte proliferation in the white matter of hemispheres and thalamus were present at autopsy in one patient who was also demented [ll]. Enlargement of the supratentnrial ventricles was present in case No. 4. The endocrine study of our patients showed decreased gonadotrophin levels in case 1. The negative LHRH test even after a 5-day administration suggests the absence of pituitary response, whereas the response to clomiphene showed slight residual function. The other 3 patients had increased gonadotrophin levels with increased response to LHRH and decreased levels of estradiol and progesterone. These findings are consistent with a primary hypogonadism. However, the post-menopausal age of patient No. 2 should be considered in interpreting these results. In one of our cases a partial deficiency of muscle cytochrome L’oxidase was found. Mitochondrial myopathies are often associated with endocri~lopathy (diabetes. hypoparathyroidism, hypogonadism) [ 121. In particular they have been seen in association with either hypothalamic infertility [13] or primary hypogonadism 1141.On the other hand, a mito~hondrial encephalomyop~~thy may account for cerebellar ataxia and also for some reported accessory features, such as dementia, retinal degeneration, epilepsy, choreoatethosis, ophthalmoplcgia, and deafness. In conclusion the occurrence of AH is probably underestimated and we suggest a careful evaluation of gonadic function in ataxic patients. Variability of onset age, of neurological picture, and of endocrine findings favours the hypothesis that AH is a heterogeneous syndrome. A thorough laboratory investigation, including neurophysiological and neuroradiological studies, may reveal a multisystemic nervous system involvement. We suggest that mitochondrial metabolism impairment may be a likely aetiology in some cases.
.4cknowledgement
Supported Ministry
by grants
from CNR
(No. 91.04180)
and
9
of Education.
References
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