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.

[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.

Partial NADH dehydrogenase defect presenting as spastic cerebral palsy.

Mitochondrial myopathies are heterogeneous disorders. They may present at any age with a variable clinical course. We report a 6-year-old boy presenting as spastic cerebral palsy for 4 years, then athetotic movements and loss of milestones. He was eventually found to have NADH dehydrogenase deficiency.

Glutaric aciduria in progressive choreo-athetosis.

The clinical symptoms in a 10-year-old girl with progressive dystonic cerebral palsy are described. The biochemical findings were dominated by large amounts of glutaric acid in the urine. The disorder is caused by impairment of the degradation of glutaryl-CoA. A survey is given of the clinical and biochemical symptoms, based on the five cases reported so far. It is concluded that patients with progressive dystonic palsy should be examined for disorders in the metabolism of organic acids.

Activation of variants of hypoxanthine-guanine phosphoribosyl transferase by the normal enzyme.

Deficient hypoxanthine-guanine phosphoribosyl transferase (HGPRT; EC 2.4.2.8) enzymes from erythrocytes of patients with hyperuricemia and with the Lesch-Nyhan syndrome migrate 15% faster in polyacrylamide gel disc electrophoresis than the normal enzyme. A half-sister of two males with partial deficiency, who had 34% of normal HGPRT activity in her erythrocytes, yielded profiles containing two distinct zones of activity; one corresponded to the enzyme found in normal individuals and one to the variant of her half-brothers. However, in her profile her variant enzyme showed notably greater activity than that observed in her half-brothers. This increase was due to an activation of the variant by normal enzyme. Electrophoresis of mixtures of normal enzyme with partially deficient enzymes from patients with hyperuricemia and with the Lesch-Nyhan syndrome also led to activation of deficient HGPRT variants by normal enzymes. Deficient variants were also activated by normal enzyme on filtration through Sephadex G-25. Experiments in which deficient variant enzymes were activated with purified normal enzyme labeled with (125)I indicated that deficient enzymes incorporate components of the normal enzyme. No such activation of deficient enzymes was ever obtained when mixtures of deficient and normal enzymes were put together in a test tube.

Purification of IMP:pyrophosphate phosphoribosyltransferases, catalytically incompetent enzymes in Lesch-Nyhan disease.

IMP:pyrophosphate phosphoribosyltransferase (IPPase) (EC 2.4.2.8) has been purified over 7000-fold from human erythrocytes. The purified enzyme moved as a single band on disc electrophoresis. Antisera prepared in rabbits and rats against the purified enzyme precipitated and neutralized the enzyme, but had no effect on AMP-pyrophosphate phosphoribosyltransferase (EC 2.4.2.7) activity. Evidence was found for isozymes (enzyme variants) of IPPase in normal erythrocytes. Erythrocyte lysates of five patients with Lesch-Nyhan disease reacted with antisera against normal IPPase. Lysates from LN erythrocytes blocked the inactivation of normal enzyme by the antibody. LN erythrocytes had about the same concentration of enzyme protein as normal erythrocytes. The genetic defect in LN results in the production of essentially normal amounts of an immunologically identifiable but catalytically incompetent enzyme. Thus LN is apparently the result of a mutation in a structural gene and is not due to deletion of a structural gene or defect in a regulatory gene.