SOD1 p.D12Y variant is associated with amyotrophic lateral sclerosis/distal myopathy spectrum.

BACKGROUND AND PURPOSE: The aim of our study was to describe patients with the p.D12Y variant (previously reported as D11Y) in SOD1 showing heterogeneous clinicopathological features. METHODS: We performed clinical, electrophysiological, magnetic resonance imaging (MRI) and muscle pathology studies in four SOD1 p.D12Y variant-positive patients. RESULTS: The SOD1 p.D12Y clinical manifestations ranged from a benign phenotype characterized by distal distribution of muscular weakness and long survival to classic forms of amyotrophic lateral sclerosis with poor prognosis. Two patients with the distal clinical phenotype showed MRI and muscle pathology alterations indicating a concurrent muscle involvement. In one of these patients significant myopathic changes were associated with rimmed vacuolar pathology. CONCLUSIONS: We expand the clinical spectrum of SOD1 p.D12Y variant, including predominant lower motor neuron forms with long survival and classic forms with aggressive course. Some patients may have concomitant distal myopathy without other explanations. Given clinical, MRI and muscle pathology alterations, SOD1 should be considered in the differential diagnosis of molecularly undefined distal myopathies with rimmed vacuoles.

Clinical and genetic heterogeneity of amyotrophic lateral sclerosis.

Although clinical picture of amyotrophic lateral sclerosis (ALS) is a stereotypical one, resulting from combination of signs secondary to dysfunction of both upper motor neuron (UMN) and lower motor neuron (LMN), clinical heterogeneity is a consistent feature of the disease. Age of onset, relative mix of UMN and LMN signs, duration of the disease and association with other conditions are major factors contributing to variable clinical phenotypes. Genetically, familial forms of ALS are associated with a large number of pleiotropic genes whose mutations impair different biochemical pathways, resulting in overlapping clinical and pathological phenotypes. Over the last few years contribution of large- and low-effect genes to sporadic ALS is increasingly recognized.

Mowat-Wilson syndrome: facial phenotype changing with age: study of 19 Italian patients and review of the literature.

Mowat-Wilson syndrome (MWS; OMIM #235730) is a genetic condition caused by heterozygous mutations or deletions of the ZEB2 gene, and characterized by typical face, moderate-to-severe mental retardation, epilepsy, Hirschsprung disease, and multiple congenital anomalies, including genital anomalies (particularly hypospadias in males), congenital heart defects, agenesis of the corpus callosum, and eye defects. Since the first delineation by Mowat et al. [Mowat et al. (1998); J Med Genet 35:617-623], approximately 179 patients with ZEB2 mutations, deletions or cytogenetic abnormalities have been reported primarily from Europe, Australia and the United States. Genetic defects include chromosome 2q21-q23 microdeletions (or different chromosome rearrangements) in few patients, and ZEB2 mutations in most. We report on clinical and genetic data from 19 Italian patients, diagnosed within the last 5 years, including six previously published, and compare them with patients already reported. The main purpose of this review is to underline a highly consistent phenotype and to highlight the phenotypic evolution occurring with age, particularly of the facial characteristics. The prevalence of MWS is likely to be underestimated. Knowledge of the phenotypic spectrum of MWS and of its changing phenotype with age can improve the detection rate of this condition.

Clinical and molecular characteristics of 1qter microdeletion syndrome: delineating a critical region for corpus callosum agenesis/hypogenesis.

BACKGROUND: Patients with a microscopically visible deletion of the distal part of the long arm of chromosome 1 have a recognisable phenotype, including mental retardation, microcephaly, growth retardation, a distinct facial appearance and various midline defects including corpus callosum abnormalities, cardiac, gastro-oesophageal and urogenital defects, as well as various central nervous system anomalies. Patients with a submicroscopic, subtelomeric 1qter deletion have a similar phenotype, suggesting that the main phenotype of these patients is caused by haploinsufficiency of genes in this region. OBJECTIVE: To describe the clinical presentation of 13 new patients with a submicroscopic deletion of 1q43q44, of which nine were interstitial, and to report on the molecular characterisation of the deletion size. RESULTS AND CONCLUSIONS: The clinical presentation of these patients has clear similarities with previously reported cases with a terminal 1q deletion. Corpus callosum abnormalities were present in 10 of our patients. The AKT3 gene has been reported as an important candidate gene causing this abnormality. However, through detailed molecular analysis of the deletion sizes in our patient cohort, we were able to delineate the critical region for corpus callosum abnormalities to a 360 kb genomic segment which contains four possible candidate genes, but excluding the AKT3 gene.

Cryptic deletions are a common finding in "balanced" reciprocal and complex chromosome rearrangements: a study of 59 patients.

Using array comparative genome hybridisation (CGH) 41 de novo reciprocal translocations and 18 de novo complex chromosome rearrangements (CCRs) were screened. All cases had been interpreted as "balanced" by conventional cytogenetics. In all, 27 cases of reciprocal translocations were detected in patients with an abnormal phenotype, and after array CGH analysis, 11 were found to be unbalanced. Thus 40% (11 of 27) of patients with a "chromosomal phenotype" and an apparently balanced translocation were in fact unbalanced, and 18% (5 of 27) of the reciprocal translocations were instead complex rearrangements with >3 breakpoints. Fourteen fetuses with de novo, apparently balanced translocations, all but two with normal ultrasound findings, were also analysed and all were found to be normal using array CGH. Thirteen CCRs were detected in patients with abnormal phenotypes, two in women who had experienced repeated spontaneous abortions and three in fetuses. Sixteen patients were found to have unbalanced mutations, with up to 4 deletions. These results suggest that genome-wide array CGH may be advisable in all carriers of "balanced" CCRs. The parental origin of the deletions was investigated in 5 reciprocal translocations and 11 CCRs; all were found to be paternal. Using customized platforms in seven cases of CCRs, the deletion breakpoints were narrowed down to regions of a few hundred base pairs in length. No susceptibility motifs were associated with the imbalances. These results show that the phenotypic abnormalities of apparently balanced de novo CCRs are mainly due to cryptic deletions and that spermatogenesis is more prone to generate multiple chaotic chromosome imbalances and reciprocal translocations than oogenesis.

Germinal mosaicism for a deletion of the FMR1 gene leading to fragile X syndrome.

Aberrant CGG trinucleotide amplification within the FMR1 gene, which spans approximately 38 Kb of genomic DNA is almost always what leads to fragile X syndrome (FXS). However, deletions of part or the entire FMR1 gene can also cause FXS. Both CGG amplification-induced silencing and deletions result in the absence of the FMR1 gene product, FMRP. Here, we report a rare case of germinal mosaicism of a deletion encompassing approximately 300 Kb of DNA, which by removing the entire FMR1 gene led to FXS. The male proband, carrying the deletion, presented in clinic with the typical features of FXS. His mother was analyzed by FISH on metaphase chromosomes with cosmid probe c22.3 spanning the FMR1 locus, and she was found not to carry the deletion on 30 analyzed cells from peripheral blood lymphocytes. Prenatal examination of the mother's third pregnancy showed that the male fetus also had the same deletion as the proband. Following this prenatal diagnosis, FISH analysis in the mother was expanded to 400 metaphases from peripheral lymphocytes, and a heterozygous FMR1 deletion was found in three. Although this result could be considered questionable from a diagnostic point of view, it indicates that the deletion is in the ovary's germinal cells.

PTPN11 mutations are not responsible for the Cardiofaciocutaneous (CFC) syndrome.

Cardiofaciocutaneous (CFC) syndrome is a multiple congenital anomalies/mental retardation syndrome characterized by congenital heart defects, characteristic facial appearance, short stature, ectodermal abnormalities and mental retardation. It was described in 1986, and to date is of unknown genetic etiology. All reported cases are sporadic, born to non-consanguineous parents and have apparently normal chromosomes. Noonan and Costello syndromes remain its main differential diagnosis. The recent finding of PTPN11 missense mutations in 45-50% of the Noonan patients studied with penetrance of almost 100% and the fact that in animals mutations of this gene cause defects of semilunar valvulogenesis, made PTPN11 mutation screening in CFC patients a matter of interest. We sequenced the entire coding region of the PTPN11 gene in ten well-characterised CFC patients and found no base changes. We also studied PTPN11 cDNA in our patients and demonstrated that there are no interstitial deletions either. The genetic cause of CFC syndrome remains unknown, and PTPN11 can be reasonably excluded as a candidate gene for the CFC syndrome, which we regard as molecular evidence that CFC and Noonan syndromes are distinct genetic entities.

Association of trisomy 9p and band heterotopia.

Patients with the trisomy 9p syndrome and CNS abnormalities have been poorly assessed. We report a patient with trisomy 9p who showed band heterotopia on MRI. Abnormal neuronal migration is sufficiently frequent in patients with the trisomy 9p syndrome that brain MRI should be routinely considered in all patients with this syndrome.

Chronic myelogenous leukemia in the course of chronic lymphocytic leukemia: evidence for an independent clonal origin.

We report on a 69-year-old man who developed Ph-positive CML 6 years after the onset of B-cell CLL. When CML was diagnosed, both malignant cell populations were detected in bone marrow and peripheral blood. Peripheral leukocytes were fractionated by Ficoll-Hypaque density gradient, and cytogenetic and molecular studies were performed on mononuclear cell and granulocyte-enriched populations. Mononuclear cells were stimulated with either PHA or PWM. In PHA-treated cultures 76% of the metaphases were Ph-negative, while after PWM stimulation 87% were Ph-positive. A bcr rearrangement was observed in DNA from the granulocyte-enriched fraction, but not in mononuclear cells. On the contrary the IgH locus resulted in monoclonally rearranged DNA, only in peripheral blood mononuclear cells. These results indicate that the two neoplastic populations originated independently.

Constitutional trisomy 8 and myelodysplasia: report of a case and review of the literature.

A diagnosis of myelodysplastic syndrome was made in an 18-year-old patient with Warkany syndrome due to constitutional trisomy 8 mosaicism. The possible causal role of this particular chromosome constitution with respect to myelodysplasia and embryonal childhood tumors is discussed.

From Pitt-Rogers-Danks syndrome to Wolf-Hirschhorn syndrome and back?

Apparently normal chromosomes without a molecular 4p16.3 deletion were found in a patient with a Wolf-Hirschhorn syndrome (WHS) phenotype. During a 10-year-period of observation he consistently presented with typical facial appearance, moderate to severe mental retardation, normal physical development with normal head circumference. Genetic results and the relatively mild clinical manifestations suggest that a diagnosis of Pitt-Rogers-Danks syndrome (PRDS) may be more likely in this patient. If WHS and PRDS will ultimately prove to be caused by haploinsufficiency of the same gene in 4p16, non-deleted patients such as the present one will be good candidates for the search of point mutations in such putative gene.

The Noonan-CFC controversy.

The Noonan syndrome and the cardio-faciocutaneous (CFC) syndrome have been described as phenotypically and genetically distinct entities. However, the resemblance between them led some authors to question the validity of this separation. We review available clinical evidence to support the opposite view, namely, that the Noonan and CFC syndromes are indeed distinct and separate conditions, both falling within the broad and causally heterogeneous spectrum of the Noonan/congenital lymphedema phenotype.

Further contribution to the description of phenotypes associated with partial 4q duplication.

We report on a 15-year-old girl with a previously undescribed de novo duplication of segment 4q13.1-->q22.2. The origin of the extrachromosomal material on 4q was unequivocally established by fluorescent in situ hybridization with a chromosome 4 painting probe. Clinical manifestations included moderate mental retardation, destructive behavior, and minor physical anomalies. An analysis of the literature on partial 4q trisomy led us to identify a region comprising bands 4q22-q23, which may be involved in the development of the acrorenal field.

Partial duplication of the long arm of chromosome 15: confirmation of a causative role in craniosynostosis and definition of a 15q25-qter trisomy syndrome.

A syndrome of mental retardation and multiple congenital anomalies, including craniosynostosis and overgrowth, was observed in two related individuals from a large kindred. Both of them carried a 15q25.1-qter trisomy associated with a subtle 13qter monosomy resulting from unbalanced segregation of a familial t(13;15)(q34;q25.1) translocation. Reportedly, a further individual in this kindred has the same condition. The present report confirms previous claims that gene(s) in the distal 15q region play a role in suture formation. At the same time it adds new data to the delineation of a 15q25-qter trisomy syndrome.

New XLMR syndrome with characteristic face, hypogenitalism, congenital hypotonia and pachygyria.

A previously unreported X-linked MCA/MR syndrome is described in 4 members of a large family. Phenotypic manifestations include mental retardation, microcephaly, failure to thrive, severe congenital hypotonia, characteristic face, hypogenitalism, pachygyria. This appears to be an X-linked dominant trait with decreased penetrance and expressivity in carrier females.

Costello syndrome: further clinical delineation, natural history, genetic definition, and nosology.

In 1977 Costello described two unrelated children with poor postnatal growth, mental retardation, curly hair, coarse face of similar appearance, and nasal papillomata, suggesting the existence of a previously undescribed syndrome of uncertain familial nature [Costello, Aust Paediatr J 13: 114-118, 1977]. The existence of this syndrome as a separate entity was substantiated several years later by two additional reports by Der Kaloustian et al. [Am J Med Genet 43:678-685, 1991] and Martin and Jones [Am J Med Genet 41:346-349, 1991]. More recently Borochowitz et al. [Am J Med Genet 43:678-685, 1992] described a new "multiple congenital anomalies/mental retardation syndrome with facio-cutaneous-skeletal involvement." Whether this condition should be considered separately from the Costello syndrome is currently a matter of debate. We present three cases, two of whom are sibs, who support the identity of the two syndromes. Our aim is to better redefine the diagnostic criteria, describe the natural history, and confirm the genetic cause of the Costello syndrome, whose pattern of inheritance is most likely autosomal recessive.

Split hand/split foot anomaly in a family segregating a balanced translocation with breakpoint on 7q22.1.

An apparently balanced translocation, t(2;7)(q21.1;q22.1) was detected in a female patient with bilateral split hand and right split foot. Split hand/split foot (SHSF) segregated as an autosomal dominant character with low penetrance in her family. The translocation was present in 6 of 13 additional relatives investigated, one of whom also had split hand on right. This observation provides further confirmation of the presence of a locus for SHSF on 7q and narrows the critical region to band 7q22.1. Defects caused by alterations of this chromosome region are variable and include manifestations of both syndromal and non-syndromal SHSF. Review of SHSF cases associated with chromosome 7 abnormalities showed a preferential involvement of the lower limbs and of the right side, suggesting the action of locally restricted developmental resistance mechanisms.

X-linked mental retardation with marfanoid habitus: first report of four Italian patients.

We report on 4 new cases of mildly retarded patients with marfanoid habitus and a characteristic constellation of minor anomalies. These patients, although sporadic, are likely to be affected by the same X-linked type of mental retardation described by Lujan et al. (American Journal of Medical Genetics 17:311-322, 1984) and more recently by Fryns and Buttiens (American Journal of Medical Genetics 28:267-274, 1987). The similar psychiatric history in 2 of our patients suggests that psychotic behaviour could be an additional manifestation, previously unrecognized in this condition. Late diagnosis of this relatively new syndrome in all our patients confirms the difficulty of the nosologic definition of mentally retarded individuals on clinical grounds alone. On the other hand, the Lujan-Fryns syndrome appears to be more common than one would have thought.

Six additional cases of the KBG syndrome: clinical reports and outline of the diagnostic criteria.

A diagnosis of KBG syndrome was made in six unrelated patients. They presented with slight mental retardation, macrodontia, and skeletal abnormalities. Microcephaly, short stature, facial anomalies, and syndactylies were also noted. The diagnostic criteria of the KBG syndrome are discussed.

"Tandem" duplication of 4p16.1p16.3 chromosome region associated with 4p16.3pter molecular deletion resulting in Wolf-Hirschhorn syndrome phenotype.

Chromosome imbalance affecting the short arm of chromosome 4 results in a variety of distinct clinical conditions. Most of them share a number of manifestations, such as mental retardation, microcephaly, pre- and post-natal growth retardation, anteverted and low-set ears, that can be considered as nonspecific signs, generally attributable to gene dosage impairment. On the other hand, more distinctive phenotypic traits correlate with the segmental aneuploidy. Duplications of the distal half of 4p give rise to the partial trisomy 4 syndrome, characterized by a "boxer" nose configuration and deep-set eyes. These signs are usually observed even in cases of small terminal duplications. Haploinsufficiency of 4p16.3 results in the so-called Wolf-Hirschhorn (WH) syndrome, a contiguous gene syndrome characterized by maxillary hypoplasia, large and protruding eyes, high nasal bridge, skeletal abnormalities, and midline defects. The smallest overlapping deletion described so far as a cause of this condition is only 165 kb long, suggesting that one or a few genes in this region act as "master" regulators of different developmental pathways. A "tandem" duplication of 4p16.1p16.3 was detected in association with a subtle deletion of 4p16.3pter on the same chromosome in a patient with the WH phenotype. The 3.2 Mb deletion, spanning the genomic region from the vicinity of D4S43 to the telomere, encompasses the recently delimited "WHS critical region" [Wright et al., 1997: Hum. Mol. Genet. 6:317-324]. This unusual chromosome rearrangement resulted in WH phenotype, clinical manifestations of partial 4p trisomy being mild or absent. This observation led us to speculate that the regulatory gene/genes in the critical WH region affect the expression of other genes in a dose-dependent manner. Haploinsufficiency of this region could be more deleterious than various partial trisomies.