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Hereditary neuropathy with liability to pressure palsies (HNPP) is an autosomal dominant disorder of the peripheral nerves leading to increased susceptibility to mechanical traction or compression. Some patients have been shown to be carriers of a 1.5-Mb deletion in chromosome 17p11.2, which corresponds to the duplicated region present in most patients with Charcot-Marie-Tooth disease type 1A. Recently, evidence has been presented that the deletion is not the only cause of HNPP. To determine the prevalence of the 1.5-Mb deletion, we have examined 22 unrelated families with HNPP in the following two ways: by polymerase chain reaction analysis of marker loci D17S122 and D17S261, and by gene dosage measurements with DNA probes for D17S122 (VAW409R3a) and D17S125 (VAW412R3a) and for the PMP-22 gene. The efficiency and sensitivity of these methods is discussed. Our results show that the prevalence of the 17p deletion in our families with HNPP is 68%. One patient, presenting as a sporadic case, was found to be affected by a de novo deletion in the paternal chromosome. Single-strand conformation analysis of the protein-coding region of the PMP-22 gene did not reveal any mutation in patients from the 7 families lacking the 17p deletion. As a group, these families could not be distinguished by clinical, electrophysiological, or morphological features from the families with the deletion.

The most frequently found mutation in autosomal dominant hereditary motor and sensory neuropathy type I (HMSN I) is a large duplication on chromosome 17p11.2 containing probes VAW409R3, VAW412R3, and EW401. We investigated a family with severe features of HMSN I, and demonstrated the absence of this duplication by a quantitative analysis of the hybridization signals of VAW409R3 and VAW412R3. Linkage analysis, however, revealed linkage with probe VAW409R3a (lod score, 3.22), which demonstrates the existence of allelic heterogeneity within the HMSN Ia locus. These findings have implications for clinical practice and for investigating the identity of the HMSN Ia gene.

To determine the functional development of children born after treatment of mild-to-moderate gestational hypertension with labetalol versus methyldopa, and no antihypertensive treatment.Historical cohort study.Twelve Dutch hospital departments of obstetrics.Live-born children born in these hospitals and prenatally exposed to labetalol, methyldopa, or bed rest because of mild-to-moderate gestational hypertension.Central nervous system development was measured with standard tests at 4-10 years of age. Linear regression techniques and Pearson's chi-square tests were used to compare the groups with regard to the outcome measures.Intelligence quotient (IQ), concentration, motor development, and behaviour at primary school age.A total of 202 children were included in the analyses. More children exposed to labetalol had attention deficit hyperactivity disorder (ADHD) than those exposed to methyldopa (OR 2.3; 95% CI 0.7-7.3), or those born to women who had been admitted for bed rest (OR 4.1; 95% CI 1.2-13.9). Sleeping problems seemed to be reported more frequently after prenatal methyldopa exposure than after exposure to labetalol (OR 3.2; 95% CI 0.6-16.7) or bed rest (OR 4.5; 95% CI 0.9-23.2), although the differences were not statistically significant. Test scores on other aspects of functional development did not differ between the three groups.In this hypothesis-generating study, labetalol exposure in utero seemed to increase the risk of ADHD among children of primary school age, whereas prenatal methyldopa exposure might influence sleep. Further studies with appropriate sample sizes are warranted to determine the long-term effects of antihypertensive medications.

A previously healthy 11-year old girl with three episodes of alternating facial palsy is described. On examination during the third relapse a severe essential hypertension was diagnosed, accompanied by abnormalities on cerebral imaging, cardiac and fundoscopic investigations. Antihypertensive treatment normalized the hypertension. No relapse of the facial palsy occurred since. The objective of this communication is to draw the attention to hypertension as a possible cause of recurrent facial paralysis in children, to stress the importance of measuring the blood pressure and taking a thorough family history in every patient presenting with facial palsy.

Hereditary deficiency of prothrombin is a rare autosomal recessive bleeding disorder, with severe bleeding diathesis in homozygotes, but rarely resulting in intracranial haematoma. We describe two infants of consanguineous parents, presenting with acute subdural haematoma. Because such haematomas in infancy are highly indicative of trauma caused by child battering and because the socio-economic status of the family was unstable, there was a suspicion of child battering. However, further investigations revealed a bleeding diathesis due to a prothrombin deficiency. DNA analysis of the prothrombin gene showed homozygosity for a novel mutation, substituting Lys for Glu at codon 7 and resulting in decreased specific clotting activity. We discuss the probability of bleeding diathesis versus child battering in the aetiology of intracranial haematoma.

Hereditary neuropathy with liability to pressure palsies (HNPP) is a disorder of the peripheral nervous system, the cause of which has recently been identified as a deletion on chromosome 17p. The deletion corresponds to the duplication that is commonly observed in patients with hereditary motor and sensory neuropathy type Ia (HMSNIa, 17p11.2–p12). Therefore, the gene for peripheral myelin protein 22 (PMP-22) is a candidate gene for both HMSNIa and HNPP. Here, we show that a similar deletion is present in one family with HNPP but is clearly absent in another family. Affected members of this family carry the expected two copies of the PMP-22 gene and the surrounding region. Furthermore, linkage analyses of this family exclude a large part of 17p, spanning the area deleted in other families with HNPP, as the location for the disease gene. These data strongly argue for the existence of genetic heterogeneity underlying HNPP. Results from two-point linkage analysis with markers on chromosome 1q are inconsistent with a possible involvement of the locus for HMSNIb in the present family.

Isolated cases of hereditary motor and sensory neuropathy type I (HMSN I, Charcot-Marie-Tooth disease type 1) have been thought to be most frequently autosomal recessive. We have found that a recently discovered duplication in chromosome 17, responsible for most cases of autosomal dominant H MSN I, is present as a de-novo mutation in 9 out of 10 sporadic patients. This finding has important implications for genetic counselling of isolated patients with HMSN I. Lancet 1992; 339: 1081-82.

The pharmacokinetics of the anti-epileptic drug di-n-propylacetate (DepakineR) have been studied in 7 patients, in whom plasma concentrations were determined during and following subchronic treatment. Elimination of the drug appeared to follow a monophasic exponential course; biological half lives were 8 to 15 hours. The data supported the assumption that an open one-compartment model can be used to describe the kinetics of dipropylacetate in man. The drug appeared to have a relatively restricted distribution: calculated relative distribution volumes ranged from 0.15 to 0.40 1/kg. There were large interindividual differences in clearance rate. The therapeutic range was considered to be between 50 and 100 mg/1 plasma. Plasma levels of phenobarbital were markedly raised during treatment with dipropylacetate for an unknown reason. Determination of the plasma concentrations of drugs at accurately fixed times appears to be a reliable method for pharmacotherapeutic monitoring of epileptic patients.

Lafora disease is a familial degenerative disorder of unknown etiology. It accounts for a small proportion of cases of myoclonus epilepsy with onset in the late first or early second decade. The main clinical manifestations are seizures, myoclonus and dementia. Although Lafora disease is considered an inborn error of the carbohydrate metabolism with typical neuropathologic features, its enzymatic defect is still unknown. Therefore, an early diagnosis is still a problem.

Metabolic encephalopathy can be the consequence of alterations in the cerebral energy metabolism (12). Generally, brains have very low energy reserves in combination with one of the highest metabolic rates of the body, especially the cerebellum. High energetic components are necessary for normal cerebral functions like maintenance of the membrane potential, transmission of impulses and biosynthetic processes (5). Certainly it is clear that cerebral function and energy metabolism are closely linked. Human brains have only 1–2 μmol glucose and 2–3 μmol glycogen per gram wet weight available as fuel, and this amount is only sufficient to subtain the normal rate of oxygen consumption for less than 5 min. This capacity is sufficient under normal circumstances or for short periods of excessive energy use, such as during epileptic seizures, but it is not adequate during prolonged hypoglycemia.

SUMMARY A seven-year-old girl with slowly progressive motor neurological impairment and high levels of lactate and pyruvate in blood and cerebrospinal fluid was found to have severe hepatic pyruvate carboxylase deficiency. However, in contrast to other patients with this deficiency, no mental retardation was apparent. Treatment with aspartic acid and thiamine over a period of seven years resulted in biochemical improvement and a stable neurological condition. The level of cognitive functioning remained the same. When treatment with aspartic acid was temporarily discontinued, lactate and pyruvate concentrations increased so markedly that the drug was resumed. This indicates that aspartic acid was the effective drug, and that the effect of thiamine was secondary. RESUME Trailement par l'acide aspartique et la thiamine chez un madade presentant une insuffisance hepatique de la pyruvate carboxylase Une insuffisance hepatique grave de la pyruvate carboxylase aete observee chez une fillette de sept ans presentant une alteration neurologique motrice lentement progressive avec des taux eleves de lactate et de pyruvate dans le sang et le LCR. Cependant, aucun retard mental n'etait apparent en contraste avec ce qui est generalement observe avec cette insuffisance. Le traitement par acide aspartique et thiamine durant une periode de sept ans s'est traduit par une amelioration biochimique et une condition neurologique stable. Le niveau des fonctions est reste le meme. Lors de l'interruption temporaire du traitement par l'acide aspartique et la thiamine, les concentrations de lactate et de pyruvate augmenterent tellement que le traitement fut immediatement repris. Ceci indique que I'acide aspartique est le medicament efficace et que l'effet de la thiamine est seulement secondaire. ZASUMMENFASSUNG Ein Patient mit Pyruvatcarboxylasemangel der Leber: Behandlung mit Asparaginsaure und Thiamin Bei einem sieben Jahre alten Madchen mit langsam fortschreitender neuromuskularer Erkrankung und hohen Laktat- und Pyruvatspiegeln im Blut und im Liquor wurde ein schwerer hepatischer Pyruvatcarboxylasemangel diagnostiziert. Im Gegensatz zu anderen Patienten mit dieser Mangelerkrankung fand sich jedoch keine geistige Retardierung. Die Behandlung mit Asparaginsaure und Thiamin iiber einen Zeitraum von sieben Jahren bewirkte eine biochemische Besserung und einen gleichbleibenden neurologischen Befund. Der cognitive Leistungsstand blieb konstant. Als die Asparaginsauretherapie vorubergehend ausgesetzt wurde, stiegen die Laktat- und Pyruvatspiegel so stark an, das das Medikament wiederangesetzt wurde. Dies deutet darauf hin, daB die Asparaginsaure das wirksame Medikament ist und das die Wirkung von Thiamin sekundar ist. RESUMEN Un paciente con deflciencia de piruvato carboxilasa del hlgado: tratamiento con acido aspartico y tiamina Una nina de siete anos de edad con alteration neurologica motora lentamente progresiva y altos niveles de lactato y piruvato en sangre y liquido cefaloraquideo, se vio que tenia una deficiencia grave de piruvato carboxilasa hepatica. Sin embargo, en contraste con otros pacientes con esta deficiencia, no habia ningun retraso mental aparente. El tratamiento con acido aspartico y tiamina durante un periodo de siete anos habia doda lugar a una mejoria bioquimica y una situation neurologica estable. El nivel de la funciones cognitivas permanecia igual. Cuando se interrumptio temporalmente el tratamiento con acido aspartico, aumentaron las concentraciones del lactato y piruvato de forma tan marcada que el tratamiento se reinstauro. Esto indica que el acido aspartico era el farmaco efectivo, y que el efecto de la tiamina era secundario.

Summary: Lafora disease is an autosomal recessive and progressive degenerative disorder of the central nervous system (CNS). The pathogenic mechanism has been presumed to be an inborn error of carbohydrate metabolism, although this has never been proved. In a case of proven Lafora disease, pyruvate metabolism, which has a central position in carbohydrate metabolism, was studied in body fluids under various conditions and in brain biopsy material. No abnormalities in this metabolic pathway were found. This finding plus earlier reports in the literature exclude a defect in glycolysis; thus, a disturbance of carbohydrate metabolism as the pathogenic mechanism of Lafora disease is unlikely RESUME La maladie de Lafora est une affection autosomique recessive degenerative et progressive du systeme nerveux central. Le mecanisme pathogenique est vraisemblablement represente par une erreur innee du metabolisme qui n'a jamais ete prouvee. Dans un cas de Lafora confirme, les auteurs ont etudie le meta-bolisme du pyruvate, qui occupe une position centrale dans le metabolisme des glucides, dans les liquides biologiques et a par-tir une biopsie cerebrale. lis n'ont pas constate anomalie dans le meltabolisme du pyruvate. Ces resultats, joints a des travaux anterieurs de la Litterature, excluent hypothese un RESUMEN La enfermedad de Lafora consiste en un proceso degenerativo del Sistema Nervioso Central de naturaleza progresiva y debido a mecanismos hereditarios autosdmicos recesivos. Los mecanismos patogenicos parecen corresponder a un defecto congenita del metabolismo de los carbohidratos a pesar de que nunca nan sido probados. En un caso de enfermedad de Lafora compro-bado patologicamente, se ha estudiado el metabolismo del piru-vato, que ocupa un lugar central en el metabolismo de los carbohidratos, en diversos fluidos corporales bajo condiciones di-versas y tambten en material cerebral de biopsia sin que se encontraran anomalfas de las vias metaolicas. Estos hallazgos unidos a informes previos de la literature excluyen un defecto en la glicolisis por lo que un trastorno en el mecanismo de los carbohidratos, como mecanismo patogenico en la enfermedad de Lafora parece improbable. ZUSAMMENFASSUNG Die Lafora-Erkrankung ist eine autosomal rezessive und progressiv-degenerative Erkrankung des ZNS. Als pathogenetischer Mechanismus wird bislang unbewiesen eine angeborene Stoning des Kohlehydratstoffwechsels vermutet. Bei einem erwiesenen Fall einer Lafora-Erkrankung wurde der Pyruvat-Metabolismus, der eine zentrale Stelle im Kohlehydrat-Metabolismus einnimmt, sowohl in Korperflussigkeiten unter unterschiedlichen Bedin-gungen als auch im bioptischen Hirngewebe untersucht. Es wur-den keine Abnormalitaten dieses Stoffwechselweges gefunden. Dies last zusammen mit alteren Berichten der Literatur einen Glycolysedefekt ausschliesen. Somit scheint eine Stoning des Kohlehydrat-Stoflwechsels als pathogenetischer Mechanismus fur die Lafora-Erkrankung unwahrscheinlich