Paroxysmal Dyskinesias Revealing 3-Hydroxy-Isobutyryl-CoA Hydrolase (HIBCH) Deficiency.

Paroxysmal dyskinesias (PD) are rare movement disorders characterized by recurrent attacks of dystonia, chorea, athetosis, or their combination, with large phenotypic and genetic heterogeneity. 3-Hydroxy-isobutyryl-CoA hydrolase (HIBCH) deficiency is a neurodegenerative disease characterized in most patients by a continuous decline in psychomotor abilities or a secondary regression triggered by febrile infections and metabolic crises.We describe two PD patients from two pedigrees, both carrying a homozygous c.913A > G, p.Thr305Ala mutation in the HIBCH gene, associated with an unusual clinical presentation. The first patient presented in the second year of life with right paroxysmal hemidystonia lasting for 30 minutes, without any loss of consciousness and without any triggering factor. The second patient has presented since the age of 3 recurrent exercise-induced PD episodes which have been described as abnormal equinovarus, contractures of the lower limbs, lasting for 1 to 4 hours, associated with choreic movements of the hands. Their neurological examination and metabolic screening were normal, while brain magnetic resonance imaging showed abnormal signal of the pallidi.We suggest that HIBCH deficiency, through the accumulation of metabolic intermediates of the valine catabolic pathway, leads to a secondary defect in respiratory chain activity and pyruvate dehydrogenase (PDH) activity and to a broad phenotypic spectrum ranging from Leigh syndrome to milder phenotypes. The two patients presented herein expand the spectrum of the disease to include unusual paroxysmal phenotypes and HIBCH deficiency should be considered in the diagnostic strategy of PD to enable adequate preventive treatment.

ECHS1 deficiency-associated paroxysmal exercise-induced dyskinesias: case presentation and initial benefit of intervention.

Paroxysmal exercise-induced dyskinesias (PED) are paroxysmal dyskinesias which manifest as dystonic movements brought on by sustained exercise. ECHS1 deficiency-induced EID was recently described by Olgiati et al. Our patient is an 8-year-old boy, who presented with intermittent episodes of stiffness and contractions affecting the legs which were always brought on by vigorous exertion. They began with curling of the toes and flexion, followed by stiffening of gait. These episodes were asymmetric, uncomfortable and often began in the left leg, often spreading to the right leg. They generally lasted for about 30-40 min. The phenomenology was noted to be dystonic affecting mostly the left leg, with equinus at the ankle and hyperextension at the knee. MRI of the brain showed regions of increased T2 and FLAIR signal and of T1 low signal in the globus pallidus bilaterally with mild diffusion restriction. Using Ambry's ExomeNextTM, an integrated exome sequencing assay, the patient was found to be heterozygous for alterations in the ECHS1 gene: missense mutations in c.518C>T (p.A173V) and c.817A>G (p.K273E). After 3 months of treatment with a mitochondrial cocktail, the patient reported that his attacks were somewhat less frequent and less severe. We decided to continue the patient on the cocktail and prescribed clonazepam 0.5 mg 1 tab to be given, as needed, for acute dystonic episodes of severe degree. The missense mutation c.817A>G has never been associated with PED before. Further, we present the first case of ECH1-associated PED with initial symptomatic improvement with a mitochondrial cocktail.

A novel mutation in the HSD17B10 gene of a 10-year-old boy with refractory epilepsy, choreoathetosis and learning disability.

Hydroxysteroid (17beta) dehydrogenase 10 (HSD10) is a mitochondrial multifunctional enzyme encoded by the HSD17B10 gene. Missense mutations in this gene result in HSD10 deficiency, whereas a silent mutation results in mental retardation, X-linked, syndromic 10 (MRXS10). Here we report a novel missense mutation found in the HSD17B10 gene, namely c.194T>C transition (rs104886492), brought about by the loss of two forked methyl groups of valine 65 in the HSD10 active site. The affected boy, who possesses mutant HSD10 (p.V65A), has a neurological syndrome with metabolic derangements, choreoathetosis, refractory epilepsy and learning disability. He has no history of acute decompensation or metabolic acidosis whereas his urine organic acid profile, showing elevated levels of 2-methyl-3-hydroxybutyrate and tiglylglycine, is characteristic of HSD10 deficiency. His HSD10 activity was much lower than the normal control level, with normal ß-ketothiolase activity. The c.194T>C mutation in HSD17B10 can be identified by the restriction fragment polymorphism analysis, thereby facilitating the screening of this novel mutation in individuals with intellectual disability of unknown etiology and their family members much easier. The patient's mother is an asymptomatic carrier, and has a mixed ancestry (Hawaiian, Japanese and Chinese). This demonstrates that HSD10 deficiency patients are not confined to a particular ethnicity although previously reported cases were either Spanish or German descendants.

Long-term follow-up and adult outcome of 6-pyruvoyl-tetrahydropterin synthase deficiency.

Little information is available on the long-term course and adult outcome of patients with 6-pyruvoyl-tetrahydropterin synthase (PTPS) deficiency. We describe the course of a 32-year-old woman with hypotonia, dystonia, choreoathetosis, mental retardation, behavioral disturbances, and incomplete puberty due to PTPS deficiency. From the age of 6 months she developed progressive hypotonia and choreoathtetoid movements despite good control of hyperphenylalaninemia. Tetrahydrobiopterin deficiency was diagnosed at age 3 years. She had a dramatic response to L-dopa, which persisted at a stable dose for 29 years. Reducing the L-dopa dose led to severe axial hypotonia and limb dystonia, and increasing it led to florid abnormal movements and behavioral disorders. This report illustrates the role of dopamine modulation in motor, psychiatric, and endocrine functions.

The kynurenine 3-hydroxylase inhibitor Ro 61-8048 improves dystonia in a genetic model of paroxysmal dyskinesia.

The effects of the novel kynurenine 3-hydroxylase inhibitor 3,4-dimethoxy-N-[4-(3-nitrophenyl)thiazol-2-yl]benzenesulfonamide (Ro 61-8048) on severity of dystonia were examined in dt(sz) mutant hamsters, an animal model of paroxysmal dystonia, in which stress precipitates dystonic episodes. Ro 61-8048 (50, 100 and 150 mg/kg i.p.) significantly reduced the severity of dystonia in dt(sz) hamsters without leading to marked central side effects. Determinations of kynurenic acid concentrations in brain homogenates demonstrated that Ro 61-8048 (100 mg/kg i.p.) provoked a two- to threefold increase of the endogeneous broad spectrum glutamate receptor antagonist kynurenic acid in the striatum, cerebellum and brainstem of mutant hamsters. The antidystonic efficacy of Ro 61-8048 at well-tolerated doses suggests that kynurenine 3-hydroxylase inhibitors should be considered as new therapeutic candidates for the treatment of dyskinesias.

Abnormal accumulation of tTGase products in muscle and erythrocytes of chorea-acanthocytosis patients.

Chorea-Acanthocytosis (CHAC) is an autosomal recessive disease characterized by neurodegeneration and acanthocytosis. Enhanced creatine kinase concentration is a constant feature of the condition. The mechanism underlying CHAC is unknown. However, acanthocytosis and enhanced creatine kinase suggest a protein defect that deranges the membrane-cytoskeleton interface in erythrocytes and muscle, thereby resulting in neurodegeneration. Acanthocytes have been correlated with structural and functional changes in membrane protein band 3--a ubiquitous anion transporter. Residue Gln-30 of band 3 serves as a membrane substrate for tissue transglutaminase (tTGase), which belongs to a class of intra- and extra-cellular Ca2+-dependent cross-linking enzymes found in most vertebrate tissues. In an attempt to cast light on the pathophysiology of CHAC, we used reverse-phase HPLC and immunohistochemistry to evaluate the role of tTGase in this disorder. We found increased amounts of tTGase-derived N(epsilon)-(-gamma-glutamyl)lysine isopeptide cross-links in erythrocytes and muscle from CHAC patients. Furthermore, immunohistochemistry demonstrated abnormal accumulation of tTGase products as well as proteinaceous bodies in CHAC muscles. These findings could explain the mechanisms underlying the increased blood levels of creatine kinase and acanthocytosis, which are the most consistent features of this neurodegenerative disease.

[Choreoacanthocytosis. A neurologic-hematologic syndrome]. / Die Choreoakanthozytose. Ein neurologisch-hämatologisches Syndrom.

A 43 year old male patient is reported who presented at the age of 33 years with a hyperkinetic movement disorder. At the time of presentation orofacial dyskinesias, tic-like hyperkinesias with vocalisation and behavioural disturbance dominated the clinical picture. In the course of his illness he developed a marked truncal choreoathetosis and a symmetrical, distal, predominantly motor polyneuropathy with wasting of lower leg muscles. Serum creatinine kinase levels were markedly elevated. Serum lipids and lipoproteins were within normal limits. These clinical features in combination with an increased number of acanthocytes, clearly visible after dilution of whole blood with normal saline (1:1), led to the diagnosis of choreoacanthocytosis (CA). Both parents were neurologically and behaviourally normal, but were found to have acanthocytes in saline diluted whole blood. The literature concerning CA is reviewed.

[Choreo-acanthocytosis]. / La chorée-acanthocytose.

We report a case of choreo-acanthocytosis in a 33 year-old man with mild chorea of the limbs but no involuntary movements of the face, areflexia, epilepsy and personality changes. Acanthocytosis was 10-20% and creatine-phosphokinase levels were raised. Electrophysiological data were consistent with lower motor neurone dysfunction. Muscle biopsy revealed changes typical of neurogenic atrophy. Nerve biopsy showed a severe loss of large myelinated axons. Electron microscopic examination was in favour of primary axonal damage affecting mainly myelinated fibers and only slightly unmyelinated fibers.

"Myopathic" changes in chorea-acanthocytosis. Clinical and histopathological studies.

Four cases of chorea-acanthocytosis were studied with special reference to muscular changes. All the cases showed the clinical stigmata of oro-linguo-facial dyskinesia with tongue biting, mild neurogenic muscular involvement and acanthocytosis. Serum creatine kinase (CK) was persistently elevated, showing MM type isozyme predominance. Histopathological studies of the peroneus brevis muscle showed prominent small group atrophy, increase of small fibers on diameter analysis, frequent angulated fibers, and angulated fibers with increased acid phosphatase activity. These findings are compatible with chronic denervation. However, central nucleation (approximately 10%) and fiber splitting (2-8%) were also found in all cases. These are compatible with myopathic changes. No correlation of these "myopathic" changes and serum CK levels was found. The "myopathic" findings are probably secondary to chronic denervation.

[Changes in lactate dehydrogenase levels in acute articular rheumatism, chorea minor and the Schönlein-Henoch syndrome in childhood]. / Variazioni del tasso della latticodeidrogenasi nel R.A.A., corea minor e sindrome di Schönlein-Henoch in età pediatrica.

Changes in serum LDH in AAR, Sydenham's chorea and purpura rheumatica and their significance were investigated in 103 cases observed at the 1st Paediatrics Clinic, University of Turin. A search was made for relation between such changes and the laboratory parameters in rheumatism. The data showed that blood LDH can be profitably determined in the diseases considered.