Expanding the clinical spectrum of MYCN-related Feingold syndrome.
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Abnormalities, Multiple↗
Biomedical subjects
Hans Scheffer
Publications and source records attributed to Hans Scheffer.
A case of neuromuscular mimicry.
Recognizing an ALS-mimic can be challenging. Here, we describe a patient with a slowly progressive dysarthria and dysphagia, with fasciculations of the tongue and general hyperreflexia, fulfilling the diagnostic criteria of 'clinical probable ALS'. Because of a non-conclusive EMG, a muscle biopsy was performed that surprisingly showed widespread nemaline rods. The clinical features and the histological findings were compatible with a sporadic late onset nemaline myopathy. Three years after initial presentation the patient died and post-mortem examination not only showed nemaline bodies in every muscle examined, but also revealed an unsuspected final diagnosis: sarcoid brainstem encephalitis. Nemaline rods can be found in various disorders, and neurosarcoidosis should be added to this list.
Amyotrophic Lateral Sclerosis↗
BSCL2 mutations in two Dutch families with overlapping Silver syndrome-distal hereditary motor neuropathy.
Mutations in the BSCL2 gene have recently been identified in families with (SPG17-linked) Silver syndrome-type hereditary spastic paraparesis as well as in families with distal hereditary motor neuropathy (HMN). We describe the first two Dutch families with BSCL2 mutations and corroborate the phenotypic variability of this gene mutation, as features compatible with Silver syndrome, variant Silver syndrome (with predominant foot rather than hand muscle involvement), distal HMN type II, or distal HMN type V were all encountered.
Adult↗
The expanding phenotype of POMT1 mutations: from Walker-Warburg syndrome to congenital muscular dystrophy, microcephaly, and mental retardation.
The importance of O-glycosylation of alpha-dystroglycan (alpha-DG) is evident from the identification of POMT1 mutations in Walker-Warburg syndrome (WWS). Approximately one-fifth of the WWS patients show mutations in POMT1, which result in complete loss of protein mannosyltransferase activity. WWS patients are characterized by congenital muscular dystrophy (CMD) with severe brain and eye abnormalities. This suggests a crucial role for alpha-DG during development of these organs and tissues. Here we report new POMT1 mutations and polymorphisms in WWS patients. In addition, we report different compound heterozygous POMT1 mutations in four unrelated families that result in a less severe phenotype than WWS, characterized by CMD with calf hypertrophy, microcephaly, and mental retardation. Compared to WWS patients, these patients have milder structural brain abnormalities, and eye abnormalities were absent, except for myopia in some cases. In these patients we postulate that one or both transcripts for POMT1 confer residual protein O-mannosyltransferase activity. Our data suggest the existence of a disease spectrum of CMD including brain and eye abnormalities resulting from POMT1 mutations.
Adolescent↗
Extended gene analysis can increase specificity of neonatal screening for cystic fibrosis.
AIM: To assess whether carriers and patients can be accurately identified by extended gene analysis for cystic fibrosis (CF) in dried blood spots. METHODS: A blinded analysis was performed in 10-mm2 blood spots on Guthrie cards, punched as if to remove material for the IRT test, from 10 CF patients and 10 carriers with known CF mutations. Genomic DNA was isolated. Aliquots of 1 microl dissolved DNA were used for subsequent PCRs. Analysis of the deltaF508 mutation was followed by an oligonucleotide ligation assay. Denaturing gradient gel electrophoresis of the whole CFTR gene was carried out in samples with only one identified mutation. Amplicons revealing an aberrant pattern were sequenced. RESULTS: In all cases, the blood-spot genotype was identical to that previously determined from whole-blood analysis. Estimated time needed to complete the procedure in a series of Guthrie cards was 3-4 wk. CONCLUSION: Extended gene analysis in dried blood spots can discriminate CF patients and carriers. If proven equally reliable in larger series, an approach to neonatal screening in which tests are only considered as screen positive when two CF mutations are found is possible. This can increase the specificity of the screening programme, and carrier detection can practically be avoided.
Algorithms↗
Neurophysiologic studies in early-onset cerebellar ataxia.
The discovery of the gene for Friedreich's ataxia (FRDA) has not only broadened the FRDA phenotype, but has also identified patients with early-onset cerebellar ataxia who resemble FRDA clinically but who do not carry a mutation in the frataxin gene. In order to identify subgroups that may represent a uniform underlying disorder, we performed neurophysiologic studies, including nerve conduction studies, electromyography, and transcranial magnetic stimulation, in 15 patients with a slowly progressive, unexplained, early-onset cerebellar ataxia (EOCA). In addition, sural nerve biopsy data were available in four patients. The neurophysiologic data identified three distinctive groups of EOCA patients: three patients with normal motor and sensory conduction velocities and borderline sensory amplitudes (group 1); three patients with a mild, predominantly motor, axonal neuropathy (group 2); and nine patients with a highly uniform syndrome characterized by pyramidal features and a severe sensory and motor axonal neuropathy (group 3). We conclude that, on the basis of neurophysiologic studies, distinctive groups of patients with EOCA can be delineated, and that differentiation between patients with EOCA can be useful for differential diagnostic consideration. Whether this splitting also reflects a fundamental phenotypic difference and, therefore, may direct future DNA studies, remains to be established.
Adult↗
Spastin mutations in sporadic adult-onset upper motor neuron syndromes.
Mutation of the spastin gene is the single most common cause of pure hereditary spastic paraparesis. In patients with an unexplained sporadic upper motor neuron (UMN) syndrome, clinical distinction between primary lateral sclerosis and sporadic hereditary spastic paraparesis may be problematic. To investigate whether spastin mutations are present in patients with primary lateral sclerosis and sporadic hereditary spastic paraparesis, we screened the spastin gene in 99 Dutch patients with an unexplained, apparently sporadic, adult-onset UMN syndrome. We found 6 mutations, of which 4 were novel, in the subgroup of 47 patients with UMN symptoms restricted to the legs (13%). Another novel spastin mutation was found in a patient with a rapidly progressive spinal and bulbar UMN syndrome that progressed to amyotrophic lateral sclerosis. In the patients with arm or bulbar UMN symptoms and slow progression, no spastin mutations were found. Our study shows that spastin mutations are a frequent cause of apparently sporadic spastic paraparesis but not of primary lateral sclerosis.
Adenosine Triphosphatases↗
Congenital cataract facial dysmorphism neuropathy syndrome: a clinically recognizable entity.
Congenital cataracts facial dysmorphism neuropathy syndrome is a recently delineated autosomal recessive condition exclusively found in the Gypsy population. Congenital cataracts facial dysmorphism neuropathy syndrome is caused by a homozygous mutation in the CTDP1 gene, leading to disruption of the ribonucleic acid transcription machinery. This report presents a young Gypsy female affected by this rare disorder. Electromyography and sural nerve histology were in accordance with a hypomyelinating neuropathy. After clinical recognition of congenital cataracts facial dysmorphism neuropathy syndrome some years ago, we recently demonstrated the presence of the homozygous IVS6+389C-->T mutation in the CTDP1 gene in this family.
Cataract↗
Mutation analysis of the entire keratin 5 and 14 genes in patients with epidermolysis bullosa simplex and identification of novel mutations.
Epidermolysis bullosa simplex is a group of blistering skin disorders caused by defects in one of the keratin genes, KRT5 and KRT14. Previously reported KRT5 and KRT14 mutations are clustered in several hotspots, namely the rod ends of the 1A and 2B domains and in the non-helical linker region L12. Therefore, genomic KRT5 and KRT14 mutation analysis was initially limited to these hotspots. In this study we describe the screening of nine EBS patients for mutations in the hotspots. In two patients, with the Koebner and the Weber-Cockayne subtypes of epidermolysis bullosa simplex respectively, we could, however, not identify any mutation in one of the hotspot domains of KRT5 and KRT14. Therefore, it appeared to be necessary to screen the entire genes for mutations. For KRT5, a complete genomic mutation detection system was previously described. We now developed a complete genomic mutation detection system for KRT14. For the amplification of the KRT14 genes, we make use of restriction sites to exempt the keratin 14 pseudogene sequence from polymerase chain reaction amplification. Using the complete genomic mutation detection system for both KRT5 and KRT14, we identified four novel KRT5 mutations (IVS1-1G>C, K404E, A438D, E475K), two of which are outside the KRT5 hotspot domains, and three novel KRT14 mutations (IVS4+1G>A, L408M, L130P).
Amino Acid Substitution↗
Holoprosencephaly, bilateral cleft lip and palate and ectrodactyly: another case and follow up.
We describe a male patient with lobar holoprosencephaly, ectrodactyly, and cleft lip/palate, a syndrome which has been seen previously in only six patients. In addition, our patient developed hypernatraemia, which has been described in three patients before.
Abnormalities, Multiple↗
Occurrence of deletion of a COL2A1 allele as the mutation in Stickler syndrome shows that a collagen type II dosage effect underlies this syndrome.
We describe a novel type of mutation in the COL2A1 gene in a family with Stickler syndrome, namely a deletion of an entire COL2A1 allele. Until now, almost all COL2A1 mutations found in this syndrome are nucleotide substitutions, small deletions, or insertions, resulting in premature translation termination. Since the phenotype in this family is not different from cases with a truncated alpha-chain, our finding supports the suggestion that a dosage effect is underlying Stickler syndrome. Moreover, in mutation screening protocols for COL2A1 one should be aware of the possibility of large deletions, which are not detected by generally used PCR-based methods.
Abnormalities, Multiple↗
Partial revertant mosaicism of keratin 14 in a patient with recessive epidermolysis bullosa simplex.
A patient with recessive epidermolysis bullosa simplex due to a previously described homozygous KRT14 1842-2A-->C splice-site mutation was re-examined, because we unexpectedly found signs of revertant mosaicism. The germline mutation resulted in different aberrant transcripts containing premature termination codons, all leading to truncated keratin 14 proteins. Basal keratinocytes in skin and in culture completely lacked keratin 14 and intermediate filaments. From this keratin 14-/- patient we started cultures from a new skin biopsy and here, we serendipitously found keratinocytes that spontaneously expressed keratin 14. This biopsy had been taken from an area of skin that was clinically affected, because blisters could simply be evoked by gentle rubbing. Immunofluorescence and electron microscopy of additional biopsies from this skin area revealed a mosaic expression of keratin 14 and reappearance of intermediate filaments in basal keratinocytes. Immunoblotting showed a revertant keratin 14 polypeptide with seemingly normal molecular weight. DNA analysis of exon 2 and its flanking intron borders showed no additional mutations in the genomic KRT14 sequence. Analysis of mRNA isolated from mosaic skin keratinocytes revealed an additional in-frame transcript (1844T-->G, 1845Delta6) that codes for an abnormal keratin 14 polypeptide with a two residue deletion and one amino acid change. The re-expression of a revertant, albeit abnormal, keratin 14 polypeptide, so-called partial revertant mosaicism, accounts for the antibody staining pattern and for the reappearance of intermediate filaments, which however, are semifunctional and not able to revert the clinical phenotype. The combination of a keratin 14-positive and a keratin 14-negative cell population in epidermis as well as in cultured keratinocytes suggests that the cellular reversion might be caused by an endogenous factor. We hypothesize that a second somatic modulating factor in the genome that affects the processing of the mutant KRT14 pre-mRNA may underlie this phenomenon.
Aged↗
Dystrophic epidermolysis bullosa inversa with COL7A1 mutations and absence of GDA-J/F3 protein.
Epidermolysis bullosa dystrophica inversa (DEB-I) is a very rare disease characterized by autosomal recessive inheritance that causes blistering and erosions on the trunk and extremities occurring in early infancy with a predilection for flexural and mucosal areas thereafter. Ultrastructural findings show dermolytic blistering and absent or rudimentary anchoring fibrils as in generalized forms of dystrophic epidermolysis bullosa. Immunoreactivity for type VII collagen, however, is preserved. We present two patients with DEB-I with compound heterozygosity for the two different COL7A1 mutations, one of them (Arg2069Cys in exon 74) carried by the heterozygous mother, the other one (Lys142Arg in exon 3) carried by the heterozygous father, accompanied by absence of the associated anchoring fibrils protein GDA-J/F3.
Adolescent↗