Distribution of alleles of the methylenetetrahydrofolate reductase (MTHFR) C677T gene polymorphism in familial spina bifida.

Spina bifida cystica (SB) is one of the most common and disabling of birth defects. Folic acid supplementation in mothers during the periconceptional period has been shown to prevent more than 70% of neural tube defects (NTD) including SB. However, the mechanism is unknown. We tested a series of multicase SB families in which 224 individuals were genotyped and a group of 215 unrelated unaffected (external) control individuals for association of SB with the T allele of methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism that produces a heat-labile enzyme protein. The data were analyzed using first the transmission/disequilibrium test (TDT) and second a modified case-control study design with Monte Carlo sampling methods. No association of SB with the MTHFR T allele was found by either method. Presently, association between SB and the T allele has been found in four studies, a Dutch study, an Irish study, a North American study, and an Italian study. But no association was found in four other studies, a British study, a French study, a Turkish study, and a German study. A California population-based study found only modestly increased risk of SB with this allele that was not significant at the P < 0.05 level. The present study finds no evidence of the association. Only one other study, the German study, has used TDT analysis. The present study is the first to use a modified case-control study design with Monte Carlo sampling methods to test this association. Thus, it appears that the MTHFR T allele is a risk factor for SB in some populations but not others. Major genetic risk factors for folate-related SB remain to be found.

Clinical manifestations of mitochondrial DNA depletion.

OBJECTIVE: We studied five new patients with mitochondrial DNA (mtDNA) depletion to better define the clinical spectrum of this disorder. BACKGROUND: mtDNA depletion has been associated with myopathy or hepatopathy, or both, in infants and young children. Involvement of the CNS and peripheral nervous system has not been clearly established. METHODS: We reviewed the clinical course and performed morphologic, biochemical, and genetic analyses of muscle samples from five patients. RESULTS: Age at onset ranged from 3 months to 5 years, and one patient survived until age 10 1/2 years. Two patients had laboratory and clinical features reminiscent of dystrophinopathy, two had evidence of brain involvement, and two had peripheral neuropathy. Muscle biopsy specimens in all patients showed abundant ragged-red fibers. Biochemistry showed cytochrome c oxidase deficiency in all patients tested and decreased activities of other respiratory chain complexes in some. CONCLUSIONS: Inheritance appeared to be autosomal recessive, suggesting that mutations in nuclear DNA are responsible for mtDNA depletion. mtDNA depletion should be considered in children with mitochondrial disorders of uncertain etiology, and criteria for diagnosis are proposed.

Dejerine-Sottas neuropathy in mother and son with same point mutation of PMP22 gene.

We studied a 25-year-old black woman with healthy parents and her 2-year, 11-month-old son. Her motor development was delayed and she started to walk with support when she was 6 years old. She never walked independently and had always used a wheelchair. Neurological evaluation showed severe weakness and atrophy of her feet, legs, and hands, bilateral pes cavus and hammertoes, corrected scoliosis, hypesthesia for proprioception and vibration sense in both feet and ankles, and areflexia. She had normal intelligence. Her son also had delayed motor milestones and was still unable to stand and walk independently at almost 3 years. Neurological evaluation revealed diffuse muscle hypotonia and weakness with generalized areflexia and normal intelligence. No muscle atrophies or feet deformities were noticed. Nerve conduction velocities showed significant slowing (less than 5 m/s) with prolonged distal latencies (above 30 ms). Compound motor action potential amplitudes were markedly reduced. Electromyography revealed polyphasic motor unit potentials. Molecular genetic studies indicated a Trembler type missense point mutation of exon 4 of the peripheral myelin protein 22 gene that led to the substitution of a spartic acid for glycine in both the mother and her son. Her parents showed normal DNA studies.

PAX genes and human neural tube defects: an amino acid substitution in PAX1 in a patient with spina bifida.

From studies in the mouse and from the clinical and molecular analysis of patients with type 1 Waardenburg syndrome, particular members of the PAX gene family are suspected factors in the aetiology of human neural tube defects (NTD). To investigate the role of PAX1, PAX3, PAX7, and PAX9, allelic association studies were performed in 79 sporadic and 38 familial NTD patients from the Dutch population. Sequence variation was studied by SSC analysis of the paired domain regions of the PAX1, PAX7, and PAX9 genes and of the complete PAX3 gene. In one patient with spina bifida, a mutation in the PAX1 gene was detected changing the conserved amino acid Gln to His at position 42 in the paired domain of the protein. The mutation was inherited through the maternal line from the unaffected grandmother and was not detected in 300 controls. In the PAX3 gene, variation was detected at several sites including a Thr/Lys amino acid substitution in exon 6. All alleles were present among patients and controls in about the same frequencies. However, an increased frequency of the rare allele of a silent polymorphism in exon 2 was found in NTD patients, but no significant association was observed (p = 0.06). No sequence variation was observed in the paired domain of the PAX7 and PAX9 genes. Our findings so far do not support a major role of the PAX genes examined in the aetiology of NTD. However, the detection of a mutation in PAX1 suggests that, in principle, this gene can act as a risk factor for human NTD.

Reduced fecundity in male ALS gene-carriers.

In order to study genetic aspects in multicase families, 89 amyotrophic lateral sclerosis (ALS) and 214 Parkinson disease (PD) kindreds were analyzed in parallel studies. Obligate gene-carriers were identified as described previously [Chatkupt et al., 1992: Am J Med Genet 44:508-512]. There were fewer children per gene-carrier male (2.42) than per gene-carrier female (3.25, Student's t-test, P < .0003) for ALS but not for other diseases. The data taken together suggest that fecundity in ALS gene-carriers was reduced in males, possibly as a result of reduced fertility. Since childbearing is usually accomplished well before the onset of neurological symptoms in ALS, and since reduced fecundity was found in male ALS gene-carriers, these findings raise the possibility that an ALS gene might have a pleiotrophic effect on fertility in males occurring decades before the onset of neurological symptoms. Evidence is presented linking reactive oxygen species to reduced fertility in males. Alternatively, decreased or nonfunctional androgen receptors could play a role.

Spinocerebellar degeneration and cerebral hypomyelination in a family.

The proband is a 24-year-old woman who developed symptoms of a spinocerebellar degeneration in early childhood. Neurological examination revealed normal cognitive function, optic atrophy, dysarthria, titubation, action tremors, increased deep tendon reflexes, Babinski's signs, and a spastic scissoring gait. The magnetic resonance imaging (MRI) showed an abnormal increased signal on long TR images involving white matter throughout the cerebral hemispheres, most striking in the subcortical white matter, and to a lesser degree in the brainstem, compatible with diffuse hypomyelinating or dysmyelinating diseases. Metabolic and chromosomal studies were normal. Her 49-year-old mother developed similar symptoms in her 20s and is now wheelchair-bound. Findings on neurological examination and MRI were similar to her daughter but more severe. The proband's maternal grandfather had a female cousin who had a neurological illness beginning in her 20s with similar symptoms and signs and died at the age of 44 years. Spinocerebellar degenerations are a group of syndromes with similar clinical manifestations but heterogeneous etiology. We report a family with spinocerebellar degeneration with distinct MRI findings compatible with hypomyelination or dysmyelination which has not heretofore been described. This family may represent a new spinocerebellar syndrome due to an abnormality of as yet an undetermined gene.

Parents do matter: genomic imprinting and parental sex effects in neurological disorders.

Genomic imprinting is a recently recognized phenomenon of differential expression of genetic material depending upon whether the genetic material has come from the male or female parent. This process of differential phenotypic expression involves mammalian development both in the normal and abnormal situations, resulting in parental sex effects. However, some parental sex effects may be due to other mechanisms such as mitochondrial inheritance. In the following article, evidence for genomic imprinting in experimental animals and in diseases are summarized. Relevant human neurological disorders manifesting parental sex effects discussed here include myotonic dystrophy, Huntington's disease, fragile X syndrome, spinocerebellar ataxia type 1, and neurofibromatosis type 1 and 2. A possible mechanism of imprinting involves the processes of methylation imprint and replication imprint. The knowledge of imprinting is helpful in clinical practice particularly in the areas of genetic counseling, prenatal diagnosis, and possible future gene therapy.

Absence of linkage between familial neural tube defects and PAX3 gene.

Neural tube defects (NTD) are among the most common and disabling birth defects. The aetiology of NTD is unknown and their genetics are complex. The majority of NTD cases are sporadic, isolated, nonsyndromic, and generally considered to be multifactorial in origin. Recently, PAX3 (formerly HuP2, the human homologue of mouse Pax-3), on chromosome 2q35-37, was suggested as a candidate gene for NTD because mutations of Pax-3 cause the mouse mutant Splotch (Sp), an animal model for human NTD. Mutations in PAX3 were also identified in patients with Waardenburg syndrome type 1 (WS1). At least eight patients with both WS1 and NTD have been described suggesting pleiotropy or a contiguous gene syndrome. Seventeen US families and 14 Dutch families with more than one affected person with NTD were collected and 194 people (50 affected) from both data sets were genotyped using the PAX3 polymorphic marker. The data were analysed using affecteds only linkage analysis. The lod scores were -7.30 (US), -3.74 (Dutch), and -11.04 (combined) at theta = 0.0, under the assumption of the autosomal dominant model. For the recessive model, the lod scores were -3.30 (US), -1.46 (Dutch), and -4.76 (combined) at theta = 0.0. Linkage between PAX3 and familial NTD was excluded to 9.9 cM on either side of the gene for the dominant model and to 3.63 cM on either side of the gene for the recessive model in the families studied. No evidence of heterogeneity was detected using the HOMOG program. Our data indicate that PAX3 is not a major gene for NTD.

Subacute combined degeneration of the spinal cord: MRI detection of preferential involvement of the posterior columns in a child.

Subacute combined degeneration of the spinal cord (vitamin B12-deficient myelopathy) is a neurologic disorder manifesting progressive symptoms of paresthesia and spastic paralysis. As shown by pathology, it initially involves the posterior columns of the thoracic cord. We present a case of vitamin B12 deficiency with preferential posterior column involvement of the thoracic cord in a child. Theoretically, this should be the earliest, most reversible stage of the disease, making recognition of this MRI pattern of critical importance.

Linkage analysis of a candidate locus (HLA) in autosomal dominant sacral defect with anterior meningocele.

Sacral defect with anterior meningocele (SDAM) is a type of caudal dysgenesis. It is present at birth and becomes symptomatic later in life, usually because of obstructive labor in females, chronic constipation, rectal fistula and abscess, or meningitis. The inheritance is autosomal dominant. HLA has been implicated in caudal dysgenesis because of analogy with disorders of the T-locus complex, a tail length determining gene in mice which is linked to the major histocompatibility complex, H-2. Members of a 5-generation family with sacral defect and anterior meningocele (SDAM) were typed with polymorphic markers (dinucleotide repeats D6S89, D6S105, D6S109, and TCTE1) linked to HLA. Two-point and multipoint analysis exclude the HLA region as the location for the SDAM gene in this family.

Paternal isodisomy for chromosome 5 in a child with spinal muscular atrophy.

Paternal isodisomy for chromosome 5 was detected in a 2-year-old boy with type III spinal muscular atrophy (SMA), an autosomal recessive degenerative disorder of alpha motor neurons, known to map to 5q11.2-13.3. Examination of 17 short-sequence repeat polymorphisms spanning 5p15.1-15.3 to 5q33.3-qter produced no evidence of maternally inherited alleles. Cytogenetic analysis revealed a normal male karyotype, and FISH with probes closely flanking the SMA locus confirmed the presence of two copies of chromosome 5. No developmental abnormalities, other than those attributable to classical childhood-onset SMA, were present. While the absence of a maternally derived chromosome 5 could have produced the symptoms of SMA through the mechanisms of genomic imprinting, the lack of more global developmental abnormalities would be unusual. Paternal transmission of two copies of a defective gene at the SMA locus seems to be the most likely cause of disease, but proof of this will have to await the identification of the SMA gene. While uniparental isodisomy is a rare event, it must be considered as a possible mechanism involved in SMA when conducting prenatal testing and counseling for this disorder.

Study of genetics, epidemiology, and vitamin usage in familial spina bifida in the United States in the 1990s.

We analyzed family structure, genetic patterns, epidemiology, and vitamin usage in a series of families with multiple cases of spina bifida (familial SB). Among 6,491 individuals ascertained in 72 families with familial SB, we identified 180 patients--85 males and 95 females. The number of collateral cases on the maternal side (49 of 3,588), analyzed by category of kinship, were significantly higher than those on the paternal side (16 of 2,903) (p = 0.0002). Genomic imprinting or a partial mitochondrial contribution are possible mechanisms for this maternal effect. The proportion of US-born SB families reporting some Irish ancestry (49%, 34 of 70) or some German ancestry (50%, 35 of 70) were significantly higher than those for the US population at large. In contrast, the proportion of families reporting some African-American ancestry (1%, 1 of 70) was significantly lower. The elevated proportions of families with Irish and German ancestry, the high frequency of SB in Northern Ireland and in certain regions of Germany, the reduced proportion of families with African-American ancestry, and the lower prevalence of SB in African-Americans all suggest a genetic contribution to the etiology of the disorder. In our study, the proportion of mothers who used supplemental vitamins during the periconceptional period (29%, 47 of 163) was not significantly different from that in the US population at large.

Myelomeningocele, spinal arteriovenous malformations and epidermal nevi syndrome: a possible rare association?

A 20-year-old woman with myelomeningocele presented with acute right-ear pain and right hemiplegia which improved, but then progressively deteriorated. Surgery, after MRI, revealed a large arteriovenous malformation (AVM) involving the right side of the upper cervical cord and brainstem. The woman also had two epidermal nevi at the same site as the spinal cord AVMs. There has been no previous report of an association of myelomeningocele, spinal cord AVMs and epidermal nevi syndrome. The same location of the nevus and spinal cord AVMs, with a proposed common pathogenesis, raise the possibility that the association may be more than chance occurrence. Spinal cord AVMs should be considered in patients with myelomeningocele and similar clinical features.

Waardenburg syndrome and myelomeningocele in a family.

We report the first family with Waardenburg syndrome type 1 and myelomeningocele in which more than one subject was affected with both disorders. The possible association is discussed. Prenatal screening for myelomeningocele is suggested for a family with Waardenburg syndrome type 1.

Parental sex effect in spina bifida: a role for genomic imprinting?

Fifty families (491 individuals in 137 sibships) with more than one living case of isolated, nonsyndromic spina bifida (SB) were analyzed genetically. There were twice as many gene-carrier females (56) as gene-carrier males (28) (P < 0.005). This was not an artifact of ascertainment bias because the sex ratio of gene-carriers was the same whether the pedigree was obtained through the proband's father or mother. Also, this effect was not observed in other disorders analyzed by the same method. Neither was the effect due to differential fertility because the number and sex of affected and unaffected children per gene-carrier parent were not different for male or female gene-carrier parents. There was no evidence that the missing male gene-carriers were lost by selective spontaneous abortion. There was no deficit of male-to-male or male-to-female transmission, excluding simple X-linked or simple mitochondrial inheritance. If genomic imprinting plays a role in the unequal female and male carrier frequencies in SB, penetrance should differ with parental sex. Penetrance was higher for offspring of female parents than of male parents, but the difference was not statistically significant. In addition, both male and female gene-carriers were frequently found in the same pedigree. Thus, the present data suggest a possible role for imprinting in SB.

Cerebellar infarction in children.

We report 3 children with posterior circulation strokes. Cerebellar infarction is rare in children; therefore, it was not the clinical diagnosis suspected primarily in 2 of these patients. The diagnostic value and limitations of neuroimaging studies, including computed tomography and magnetic resonance imaging, in cerebellar infarction in children are discussed. Because 3 patients were examined in a 2 year period in one institution, this entity may be more prevalent than generally believed and should be considered in the differential diagnosis of posterior fossa lesions in children.