Childhood Pompe disease: clinical spectrum and genotype in 31 patients.

BACKGROUND: As little information is available on children with non-classic presentations of Pompe disease, we wished to gain knowledge of specific clinical characteristics and genotypes. We included all patients younger than 18 years, who had been evaluated at the Pompe Center in Rotterdam, the Netherlands, between 1975 and 2012, excluding those with the classic-infantile form. None were treated with enzyme replacement therapy at the time of evaluation. We collected information on first symptoms, diagnosis, use of a wheelchair and/or respirator, and enzyme and mutation analysis and assessed muscle strength, pulmonary function, and cardiac parameters. RESULTS: Thirty-one patients participated. Median age at symptom onset was 2.6 years (range 0.5-13y) and at diagnosis 4.0 years. Most first problems were delayed motor development and problems related to limb-girdle weakness. Fatigue, persistent diarrhea and problems in raising the head in supine position were other first complaints. Ten patients were asymptomatic at time of diagnosis. Five of them developed symptoms before inclusion in this study. Over 50 % of all patients had low or absent reflexes, a myopathic face, and scoliosis; 29 % were underweight. Muscle strength of the neck flexors, hip extensors, hip flexors, and shoulder abductors were most frequently reduced. Pulmonary function was decreased in over 48 % of the patients; 2 patients had cardiac hypertrophy. Patients with mutations other than the c.-32-13T > G were overall more severely affected, while 18 out of the 21 patients (86 %) with the c.-32-13T > G/'null' genotype were male. CONCLUSIONS: Our study shows that Pompe disease can present with severe mobility and respiratory problems during childhood. Pompe disease should be considered in the differential diagnosis of children with less familiar signs such as disproportional weakness of the neck flexors, unexplained fatigue, persistent diarrhea and unexplained high CK/ASAT/ALAT. Disease presentation appears to be different from adult patients. The majority of affected children with GAA genotype c.-32-13T > G/'null' appeared to be male.

Clinical findings and a therapeutic trial in the first patient with beta-ureidopropionase deficiency.

The clinical, neurophysiological and neuroradiological work-up as well as the results of a specific treatment trial are presented of the first patient diagnosed with beta-ureidopropionase deficiency (E.C. 3.5.1.6, McKusick 606673). The patient presented with an early-onset dystonic movement disorder, severe developmental delay with marked impairment of visual responsiveness in combination with severely delayed myelination in magnetic resonance imaging studies. In addition, there were partial optic atrophy, pigmentary retinopathy and mild cerebellar hypoplasia. The enzyme defect was expected to lead to intracerebral deficiency of beta-alanine which seems to be a neuromodulator at inhibitory synapses. Therefore, a therapeutic trial with supplementation of beta-alanine was undertaken over 1.5 years with no convincing clinical improvement.

Sleep-disordered breathing and respiratory failure in acid maltase deficiency.

BACKGROUND: Sleep-disordered breathing (SDB) and respiratory failure (RF) are complications of acid maltase deficiency (AMD), a rare hereditary myopathy. OBJECTIVE: To define the relationship between lung and respiratory muscle function, to establish incidence and patterns of SDB, and to determine daytime predictors of SDB. METHODS: Sitting and supine lung and respiratory muscle function tests were obtained in 27 subjects with juvenile and adult AMD (aged 39 +/- 19 years) and compared with outcomes of polysomnography. RESULTS: Ventilatory restriction was present in 17/27 subjects. Inspiratory vital capacity (IVC) correlated (p < 0.005) with peak inspiratory muscle pressure (PIP, R = 0.61), respiratory muscle strain (P(0.1)/P(0.1max), R = -0.68), and gas exchange by day (PaO(2): R = 0.71; PaCO(2): R = -0.64) and night (SaO(2): R = 0.73; P(tc)CO(2): R = -0.75). Diaphragm weakness (DW) was present in 13 subjects, 10 of whom had hypercapnic RF (PaCO(2) 65 +/- 7 mm Hg), and was associated with longer disease course. SDB was found in 13 subjects, 12 with DW. It was characterized by REM-sleep hypopneas that, as ventilatory restriction worsened, were complemented by hypoventilation (P(tc)CO(2) > 50 mm Hg) first in REM sleep, then in non-REM sleep (p < 0.005). SDB was predicted by DW (sensitivity 80%, specificity 86%) and nocturnal hypoventilation by IVC < 40% (sensitivity 80%, specificity 93%). Noninvasive ventilation, instituted for daytime respiratory failure or nocturnal hypoventilation, normalized daytime and nocturnal gas exchange (p < 0.005). CONCLUSION: Vital capacity correlates with respiratory muscle function in AMD. Diaphragm weakness is the major cause of SDB and RF. SDB and nocturnal hypoventilation are predictable from daytime function tests.

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.

Hereditary motor and sensory neuropathy--Lom (HMSNL): refined genetic mapping in Romani (Gypsy) families from several European countries.

Hereditary motor and sensory neuropathy type Lom, initially identified in Roma (Gypsy) families from Bulgaria, has been mapped to 8q24. Further refined mapping of the region has been undertaken on DNA from patients diagnosed across Europe. The refined map consists of 25 microsatellite markers over approximately 3 cM. In this collaborative study we have identified a number of historical recombinations resulting from the spread of the hereditary motor and sensory neuropathy type Lom gene through Europe with the migration and isolation of Gypsy groups. Recombination mapping and the minimal region of homozygosity reduced the original 3 cM hereditary motor and sensory neuropathy type Lom region to a critical interval of about 200 kb.

Combined enzymatic complex I and III deficiency associated with mutations in the nuclear encoded NDUFS4 gene.

Combined OXPHOS-system enzyme deficiencies are observed in approximately 25% of all OXPHOS-system disturbances. Of these, combined complex I and III deficiency is relatively scarce. So far, only mtDNA and thymidine phosphorylase (TP) mutations have been associated with combined OXPHOS-system disturbances. In this report we show, for the first time, that a nuclear gene mutation in a structural, nuclear encoded complex I gene is associated with combined complex I and III deficiency. After our initial report we describe mutations in the NDUFS4 gene of complex I in two additional patients. The first mutation is a deletion of G at position 289 or 290. Amino acid 96 changes from a tryptophan to a stop codon. The mutation was found homozygous in the patient; both parents are heterozygous for the mutation. The second mutation is a transition from C to T at cDNA position 316. Codon is changed from CGA (arginine) to TGA (stop). The patient is homozygous for the mutation; both parents are heterozygous. Both mutations in the NDUFS4 gene led to a premature stop in Leigh-like patients with an early lethal phenotype. We hypothesise that the structural integrity of the OXPHOS system, in mammal supermolecular structures, may be responsible for the observed biochemical features.

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.

Localization of laminin isoforms in the guinea pig cochlea.

OBJECTIVE: To elucidate the pathogenesis of inner ear disorders by examining the distribution of a major component of basement membranes, the glycoprotein laminin. STUDY DESIGN: Animal model. METHODS: Adult guinea pig cochleae were fixed with methanol and sectioned. Sections were examined for the presence of laminins alpha2, alpha5, beta1, and gamma1 using immunohistochemistry. RESULTS: Laminins alpha2, alpha5, and beta1 were not detected. Laminin gamma1 was found in the limbus, spiral ligament, and stria vascularis. CONCLUSIONS: Anti-laminin antibodies have been found in patients with inner ear disorders. Laminin gamma1 demonstrates specific staining at multiple sites in the guinea pig cochlea. These structures may be targets of antibodies causing sensorineural hearing loss.

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.

Fetal CNS damage after exposure to maternal trauma during pregnancy.

Nine case reports are presented to indicate the possible effects of maternal trauma on surviving fetuses. Previous reports have only addressed fatal consequences. Traumata occurred between gestational weeks 23 and 37. Seven mothers had motor-vehicle accidents (MVA), two had blunt abdominal traumata. Four mothers suffered severe injuries, such as cerebral contusion, fractures or placental abruption leading to emergency Cesarean section. Premature uterine contractions were observed in five mothers and hemorrhage in two. The nine children were born after 30 to 40 weeks of gestation. Seven had normal postpartal vital signs, one required resuscitation and one premature needed assisted ventilation. Clinical symptoms were variable: movement disorders (n = 3), hydrocephalus (n = 2), convulsions (n = 1), cerebral palsy (n = 1), and normal (n = 3). Follow-up ranged from 7 months to 5 years. Neuroimaging revealed periventricular leukomalacia (n = 2), localized vascular infarctions (n = 2), hemorrhage (n = 1), hydrocephalus (n = 2) and global damage (n = 1). The causative role of maternal accidents was extremely likely in one patient, and probable but unproved in the remaining cases.