Optico-cochleo-dentate degeneration associated with severe peripheral neuropathy and caused by peroxisomal D-bifunctional protein deficiency.

The clinical, neuroradiological, neuropathological and biochemical findings in a patient with optico-cochleo-dentate degeneration (OCDD; OMIM 258700) are presented in a severe case succumbing at the age of 4 years. The electron microscopic and biochemical data showed for the first time that OCDD may occur as the phenotypic expression of D-bifunctional protein deficiency, i.e., a peroxisomal disorder. The boy was born as the first child of healthy, consanguineous parents of Turkish origin. No other family members were affected. The main clinical symptoms consisted of muscle hypotonia ("floppy infant"), generalized epileptic fits, hypacusis, rotatory nystagmus, insufficient pupillary reactions, and mental retardation. Fibroblast cultures revealed D-bifunctional protein deficiency. Neuropathological examination displayed moderate frontoparietal and insular microgyria, and atrophy of the cerebellum. Loss of neurons was severe in the granular layer, the Purkinje cell band of the cerebellum, and rather complete in the dentate nucleus. A corresponding loss of myelinated fibers associated with characteristic periodic acid-Schiff-positive macrophages was most prominent in the white matter of the cerebellum. There was additional severe loss of myelinated fibers in the central portions of the optic nerve, reduction of the nerve fiber density in the cochlear nerve, and reduction of myelinated nerve fibers by about 80-90% in the sural nerve, which has not been studied in previous cases. At the electron microscopic level, characteristic inclusions mainly in perivascular macrophages and astrocytes were the most prominent finding. The inclusions usually showed a bilaminar structure, whereas trilaminar structures, typically seen in adrenoleukodystrophy, and multilaminar structures were less frequently seen.

beta-Ureidopropionase deficiency: a novel inborn error of metabolism discovered using NMR spectroscopy on urine.

In this work, NMR investigations that led to the discovery of a new inborn error of metabolism, beta-ureidopropionase (UP) deficiency, are reported. 1D (1)H-NMR experiments were performed using a patient's urine. 3-Ureidopropionic acid was observed in elevated concentrations in the urine spectrum. A 1D (1)H-(1)H total correlation spectroscopy (TOCSY) and two heteronuclear 2D NMR techniques (heteronuclear multiple bond correlation (HMBC) and heteronuclear single-quantum correlation (HSQC)) were used to identify the molecular structure of the compound that caused an unknown doublet resonance at 1.13 ppm. Combining the information from the various NMR spectra, this resonance could be assigned to 3-ureidoisobutyric acid. These observations suggested a deficiency of UP. With 1D (1)H-NMR spectroscopy, UP deficiency can be easily diagnosed. The (1)H-NMR spectrum can also be used to diagnose patients suffering from other inborn errors of metabolism in the pyrimidine degradation pathway.

Autosomal dominant distal myopathy: further evidence of a chromosome 14 locus.

In 1995 Laing et al. (Am J Hum Genet 56(1995)422) described a single family with nine members affected by an autosomal dominant infantile onset distal myopathy. This family generated a LOD score of 2.6 for a locus on chromosome 14. We describe two families with an infantile onset distal myopathy: a new family with four affected members and the family previously described by Scoppetta et al. (Acta Neurol Scand 92(1955)122) in both of which haplotype segregation was compatible with linkage to the same chromosome 14 locus, generating LOD scores of 0.9 at a penetrance of 100% for the markers D14S283 and D14S64 (theta=0) in both families. The loci for autosomal recessive hereditary inclusion body myopathy and Nonaka myopathy on chromosome 9 and for autosomal dominant distal myopathy of Markesberry-Griggs and Udd on chromosome 2q31-33 were excluded by linkage analysis. The disease followed a uniform course with selective wasting of the anterior tibial muscles, starting in infancy and recognizable by a characteristic clinical sign of the 'hanging big toe'. This was followed by slow progression, with involvement of the finger and wrist extensor muscles in the third decade and proximal limb muscles in the fourth decade. Interestingly, we also found evidence of an accompanying mild peripheral neuropathy in the oldest individual with hypomyelination of numerous large myelinated fibres. In addition, this patient's muscle biopsy also showed autophagic vacuoles and numerous intranuclear tubulo-filamentous inclusions of 15-20 nm diameter. Given that all three families with infantile onset distal myopathy are compatible with linkage to the same locus on chromosome 14, this study supports evidence for, and enlarges the clinical and neuropathological spectrum of the distal myopathy on chromosome 14.

Detection of beta-ureidopropionase deficiency with HPLC-electrospray tandem mass spectrometry and confirmation of the defect at the enzyme level.

The pyrimidine bases uracil and thymine are degraded via the consecutive action of three enzymes to beta-alanine and beta-aminoisobutyric acid, respectively. To date, a number of patients have been described with a deficiency of dihydropyrimidine dehydrogenase and dihydropyrimidinase, the first two enzymes of the pyrimidine degradation pathway. In this study, we demonstrate that the first patient presenting with N-carbamyl-beta-amino aciduria, due to a deficiency of beta-ureidopropionase, was easily diagnosed at the metabolite level using HPLC-tandem mass spectrometry. Urinary analysis showed strongly elevated levels of N-carbamyl-beta-alanine and N-carbamyl-beta-aminoisobutyric acid, with normal or moderately increased levels of the pyrimidine bases and the dihydropyrimidines, respectively. The deficiency of beta-ureidopropionase was confirmed by measuring all three enzymes of the pyrimidine degradation pathway. No activity of beta-ureidopropionase could be detected in a liver biopsy of the patient, while a normal activity of dihydropyrimidine dehydrogenase and dihydropyrimidinase was present. Thus, HPLC-tandem mass specrometry proved to be a powerful tool for the initial diagnosis of patients with deficiency of beta-ureidopropionase.

Syndrome of gingival hypertrophy, hirsutism, mental retardation and brachymetacarpia in two sisters: specific entity or variant of a described condition?

Two sisters born to consanguineous Lebanese parents had mental retardation and epilepsy, brachymetacarpalia, hirsutism, bulbous soft nose, thick floppy ears with abnormal configuration and gingival hypertrophy. One girl presented additionally with tetralogy of Fallot and the other with congenital hypothyroidism and bilateral ureteral stenosis. These manifestations resemble the syndrome of hypertrichosis-gingival fibromatosis-mental retardation and seizures of Anavi et al. [1989: Dev Med Child Neurol 31:538-542] but our two girls additionally have brachymetacarpia. The inheritance seems to be autosomal recessive. These two sisters may represent a hitherto undescribed syndrome. We discuss the findings in our patients in relation to the literature.

Hydrocephalus internus in two patients with 5,10-methylenetetrahydrofolate reductase deficiency.

Hydrocephalus internus (HCI) of all four ventricles in association with early neurological abnormalities is described as the presenting symptom in two patients with 5,10-methylenetetrahydrofolate reductase (MTHFR) deficiency. Decreased activity of MTHFR leads to reduction of 5-methyltetrahydrofolate, the main methyl donor for methionine synthesis necessary for synthesis of S-adenosyl-methionine (SAM). Demyelination in MTHFR deficiency has been attributed to low SAM levels in the brain. The biochemical hallmarks of the disorder are hyperhomocystinemia, homocystinuria and low levels of plasma methionine. Hydrocephalus internus requiring neurosurgical intervention has to our knowledge not been reported as a presenting feature of homocystinuria due to deficiency of MTHFR so far. The surprising finding of HCI of all four ventricles in MTHFR deficiency must be kept in mind when evaluating patients with hydrocephalus of unknown origin.

cDNA cloning, genomic structure and chromosomal localization of the human BUP-1 gene encoding beta-ureidopropionase.

A full-length cDNA clone encoding human beta-ureidopropionase was isolated. A 1152-nucleotide open reading frame which corresponds to a protein of 384 amino acids with a calculated molecular weight of 43¿ omitted¿158 Da, surrounded by a 5'-untranslated region of 61 nucleotides and a 3'-untranslated region of 277 nucleotides was identified. The protein showed 91% similarity with the translation product of the rat beta-ureidopropionase cDNA. Expression of the human cDNA in an Escherichia coli and eukaryotic COS-7 expression system revealed a very high beta-ureidopropionase enzymatic activity, thus confirming the identity of the cDNA. Since human EST libraries from brain, liver, kidney and heart contained partial beta-ureidopropionase cDNAs, the enzyme seems to be expressed in these tissues, in agreement with the expression profile of this enzyme in rat. Using the human cDNA as a probe a genomic P1 clone could be isolated containing the complete human beta-ureidopropionase gene. The gene consist of 11 exons spanning approximately 20 kB of genomic DNA. Fluorescence in situ hydridization localized the human beta-ureidopropionase gene to 22q11.2.

Megalencephaly, mega corpus callosum, and complete lack of motor development: a previously undescribed syndrome.

We report on 3 sporadic cases of in utero onset megalencephaly. Children were born to healthy nonconsanguineous parents after uneventful pregnancies. Head circumferences were just above the 97th centile at birth in 2 patients, 2 cm above the 97th centile in 1 patient, and subsequently increased to 4.5-6.5 cm above the 97th centile at age 5 years. All patients completely lacked motor and speech development and showed very little intellectual progress. There was a distinctive facial aspect with frontal bossing, low nose bridge, and large eyes, but no cutaneous abnormalities and no signs of other organ involvement. Magnetic resonance imaging showed bilateral megalencephaly with a broad corpus callosum, enlarged white matter, and focally thick gray matter, resulting in pachygyric appearance of the cortex. Opercularization was incomplete, and the Sylvian fissures were wide. Somatosensory evoked potentials in 1 patient showed normal latencies of cervical and contracortical potentials but bilaterally increased cortical amplitudes. To the best of our knowledge, no similar case observations have been recorded previously.

HMSNL in a 13-year-old Bulgarian girl.

We present a 13-year-old Bulgarian girl with a new form of demyelinating neuropathy with hearing loss. The clinical and neuropathological features of the patient were similar to those of the recently described hereditary motor and sensory neuropathy type Lom (HMSNL), first identified in a large Bulgarian Gypsy population. Neuropathological examination of a peripheral nerve biopsy revealed an excess of nerve fibres with inappropriately thin myelin sheaths compared with the axon diameter, surrounded by concentric Schwann cells without typical onion-bulb formation. The parents of our patient are unaware of Gypsy ancestry and are not in a consanguineous marriage. Genetic analyses showed that the patient was homozygous for the predominant HMSNL haplotype on 8q24. Our findings indicate that HMSNL should be considered in the differential diagnosis of any patient presenting with the symptoms of demyelinating neuropathy with hearing loss, even if no Gypsy ethnic background is reported.

Acute cerebellitis with near-fatal cerebellar swelling and benign outcome under conservative treatment with high dose steroids.

Acute cerebellar swelling is an emergency because of brainstem compression as well as upward or downward cerebellar herniation. Few childhood cases are on record, with fatal outcome in three out of six. We report a girl with probable Epstein-Barr virus-associated cerebellar swelling who recovered completely with steroid treatment after a stormy course. Review of the literature showed that all three patients, including our own, who recovered fully, received high-dose steroids in contrast to none of the four patients who died or survived with sequelae. Neuroimaging and evoked potential studies are useful for early diagnosis and disease monitoring. We conclude that for the time being high-dose steroid treatment is advocated in patients with acute infectious or parainfectious cerebellar swelling.

Congenital microgastria, growth hormone deficiency and diabetes insipidus.

UNLABELLED: Microgastria is a rare malformation of the stomach always associated with variable patterns of malformations of the lung, heart, aortic arch, skeleton, and central nervous system. Many cases present with asplenia and hepatic symmetry as well as intestinal malrotation. We report a first case of a 4.5-year-old girl with congenital microgastria in association with growth hormone deficiency, diabetes insipidus, brachyoesophagus, hernia of the diaphragm, gastro-oesophageal reflux, intestinal malrotation, enlarged symmetrical liver, asplenia, as well as mental and statomotor retardation. CONCLUSION: Congenital microgastria is always associated with malformations of other organs. Patients at any age presenting one of the symptoms: failure to thrive, vomiting, asplenia, midline defects and parts of the VACTERL association should be carefully examined to exclude microgastria.

[Nervous system manifestations in HIV infected children]. / Affektionen des Nervensystems bei perinatal HIV-infizierten Kindern.

In 34 perinatally HIV infected children time of manifestation, type and treatability of neurologic disorders were investigated for a period of 7 years (1987-1994). Neurological investigations were done every 6 months; EEG and MRI/CT were examined initially in the asymptomatic stage and were repeated when neurologic Symptoms occurred. Zidovudine therapy was started after onset of symptoms, dosage was raised, when treatment with Zidovudine had already begun (600-720 mg/m2/day). Various neurological manifestations were seen in 4 of 12 patients in stage B (33%) and in 11 of 14 children in AIDS (80%). 7 of the 14 AIDS-patients (50%) developed a subacute progressive course or progressive plateau course and 4 of 14 (30%) a static course of encephalopathy. Pathological changes in EEG were seen in 54% of investigated patients with neurological deficits. Neuroimaging revealed pathological findings in all symptomatic subjects, 6 of 11 patients in AIDS (55%) has a severe general cerebral atrophy and multifocal white matter lesions. Zidovudine had a positive temporary effect from 6 to 12 months in 5 of 11 treated patients (45%). At present a thorough neurological examination is the most sensitive method to detect neurological impairment in HIV infected children. In most cases CT/MRI scan provides information about the course of the encephalopathy. Antiretroviral therapy has a limited benefit, if neurologic symptoms start after the second year of life.