MSTO1 mutations cause mtDNA depletion, manifesting as muscular dystrophy with cerebellar involvement.

MSTO1 encodes a cytosolic mitochondrial fusion protein, misato homolog 1 or MSTO1. While the full genotype-phenotype spectrum remains to be explored, pathogenic variants in MSTO1 have recently been reported in a small number of patients presenting with a phenotype of cerebellar ataxia, congenital muscle involvement with histologic findings ranging from myopathic to dystrophic and pigmentary retinopathy. The proposed underlying pathogenic mechanism of MSTO1-related disease is suggestive of impaired mitochondrial fusion secondary to a loss of function of MSTO1. Disorders of mitochondrial fusion and fission have been shown to also lead to mitochondrial DNA (mtDNA) depletion, linking them to the mtDNA depletion syndromes, a clinically and genetically diverse class of mitochondrial diseases characterized by a reduction of cellular mtDNA content. However, the consequences of pathogenic variants in MSTO1 on mtDNA maintenance remain poorly understood. We present extensive phenotypic and genetic data from 12 independent families, including 15 new patients harbouring a broad array of bi-allelic MSTO1 pathogenic variants, and we provide functional characterization from seven MSTO1-related disease patient fibroblasts. Bi-allelic loss-of-function variants in MSTO1 manifest clinically with a remarkably consistent phenotype of childhood-onset muscular dystrophy, corticospinal tract dysfunction and early-onset non-progressive cerebellar atrophy. MSTO1 protein was not detectable in the cultured fibroblasts of all seven patients evaluated, suggesting that pathogenic variants result in a loss of protein expression and/or affect protein stability. Consistent with impaired mitochondrial fusion, mitochondrial networks in fibroblasts were found to be fragmented. Furthermore, all fibroblasts were found to have depletion of mtDNA ranging from 30 to 70% along with alterations to mtDNA nucleoids. Our data corroborate the role of MSTO1 as a mitochondrial fusion protein and highlight a previously unrecognized link to mtDNA regulation. As impaired mitochondrial fusion is a recognized cause of mtDNA depletion syndromes, this novel link to mtDNA depletion in patient fibroblasts suggests that MSTO1-deficiency should also be considered a mtDNA depletion syndrome. Thus, we provide mechanistic insight into the disease pathogenesis associated with MSTO1 mutations and further define the clinical spectrum and the natural history of MSTO1-related disease.

Clinical and genetic complexity of Mitchell-Riley/Martinez-Frias syndrome.

Mitchell-Riley syndrome/Martinez-Frias syndrome (MRS/MFS) is a rare, autosomal recessive disorder with multisystem involvement and poor prognosis. Most reported cases have been associated with homozygous or compound heterozygous mutations in the RFX6 gene, a transcriptional regulatory factor for pancreatic morphogenesis. Given the limited number of reported cases, the syndrome may be under-recognized. When the particular phenotype of MFS includes a mutation on the RFX6 gene and neonatal diabetes, it has been called Mitchell-Riley syndrome. Because of this, we propose that MFS/MRS is a symptom continuum or an RFX6 malformation complex. We report an infant with all of the key clinical features of MRS/MFS without a definable mutation in RFX6 gene, supporting the consideration of these features as a symptom complex, and raising the question of genetic heterogeneity.

Refinement of the Region for Split Hand/Foot Malformation 5 on 2q31.1.

Background: Deletions that encompass 2q31.1 have been proposed as a microdeletion syndrome with common clinical features, including intellectual disability/developmental delay, microcephaly, cleft palate, growth delay, and hand/foot anomalies. In addition, several genes within this region have been proposed as candidates for split hand-foot malformation 5 (SHFM5). Methods: To delineate the genotype-phenotype correlation between deletions of this region, we identified 14 individuals with deletions at 2q31.1 detected by microarray analysis for physical and developmental disabilities. Results: All subjects for whom detailed clinical records were available had neurological deficits of varying degree. Seven subjects with deletions encompassing the HOXD cluster had hand/foot anomalies of varying severity, including syndactyly, brachydactyly, and ectrodactyly. Of 7 subjects with deletions proximal to the HOXD cluster, 5 of which encompassed DLX1/DLX2, none had clinically significant hand/foot anomalies. In contrast to previous reports, the individuals in our study did not display a characteristic gestalt of dysmorphic facial features. Conclusion: The absence of hand/foot anomalies in any of the individuals with deletions of DLX1/DLX2 but not the HOXD cluster supports the hypothesis that haploinsufficiency of the HOXD cluster, rather than DLX1/DLX2, accounts for the skeletal abnormalities in subjects with 2q31.1 microdeletions.

Phenotypic variability in 49 cases of ESCO2 mutations, including novel missense and codon deletion in the acetyltransferase domain, correlates with ESCO2 expression and establishes the clinical criteria for Roberts syndrome.

BACKGROUND: Roberts syndrome (RBS) and SC phocomelia are caused by mutations in ESCO2, which codes for an acetyltransferase involved in the regulation of sister chromatid cohesion. Of 26 mutations described to date, only one missense mutation has been reported and all others are predicted to be truncating mutations. Genotype-phenotype analysis has been hampered by limited numbers of patients with clinical information available. OBJECTIVE: To provide unpublished clinical data for 31 patients with proven ESCO2 mutations and combine this series with previously reported clinical and mutation data on 18 cases. Methods Genotype-phenotype correlations and functional effects of two novel ESCO2 mutations were analysed. In situ hybridisation on human embryos at Carnegie stages 14, 17 and 21 was performed to study ESCO2 expression during development. RESULTS AND CONCLUSIONS: Using the cohort of 49 patients, the clinical criteria for RBS were delineated to include: growth retardation; symmetric mesomelic shortening of the limbs in which the upper limbs are more commonly and severely affected than the lower limbs; characteristic facies with microcephaly. The severity of malformations of the facies correlates with the severity of limb reduction. The occurrence of corneal opacities may be associated with specific mutations. Two new mutations, both in the ESCO2 acetyltransferase domain, are described and their acetylation effects in vitro demonstrated. In situ hybridisation on human embryos showed ESCO2 expression in the brain, face, limb, kidney and gonads, which corresponds to the structures affected in RBS.

Discordant PKU phenotype in one family due to disparate genotypes and a novel mutation.

Classical phenylketonuria (PKU) and mild hyperphenylalaninaemia (MHP) are two ends of the broad diagnostic spectrum in phenylalanine hydroxylase (PAH) deficiency. We have analysed a family in which classical PKU, MHP and a normal phenotype occurred in family members with different mutations. Sequence analysis revealed three mutations segregating in the family. The individual with classical PKU had two previously reported deleterious mutations. A third novel mutation was identified in the other two individuals. This report demonstrates that when discordant phenotypes occur in a family, without protein loading or phenylalanine tolerance test, complete analysis of the PAH gene may be performed in order to support the diagnosis and assist in accurate genetic counselling and patient management.

Partial paternal uniparental disomy of chromosome 6 in an infant with neonatal diabetes, macroglossia, and craniofacial abnormalities.

Neonatal diabetes, which can be transient or permanent, is defined as hyperglycemia that presents within the first month of life and requires insulin therapy. Transient neonatal diabetes mellitus has been associated with abnormalities of the paternally inherited copy of chromosome 6, including duplications of a portion of the long arm of chromosome 6 and uniparental disomy, implicating overexpression of an imprinted gene in this disorder. To date, all patients with transient neonatal diabetes mellitus and uniparental disomy have had complete paternal isodisomy. We describe a patient with neonatal diabetes, macroglossia, and craniofacial abnormalities, with partial paternal uniparental disomy of chromosome 6 involving the distal portion of 6q, from 6q24-qter. This observation demonstrates that mitotic recombination of chromosome 6 can also give rise to uniparental disomy and neonatal diabetes, a situation similar to that observed in Beckwith-Wiedemann syndrome, another imprinted disorder. This finding has clinical implications, since somatic mosaicism for uniparental disomy of chromosome 6 should also be considered in patients with transient neonatal diabetes mellitus.

Duchenne/Becker muscular dystrophy: correlation of phenotype by electroretinography with sites of dystrophin mutations.

The dark-adapted electroretinogram (ERG) of patients with Duchenne and Becker muscular dystrophy (DMD/BMD) shows a marked reduction in b-wave amplitude. Genotype-phenotype studies of mouse models for DMD show position-specific effects of the mutations upon the phenotype: mice with 5' defects of dystrophin have normal ERGs, those with defects in the central region have a normal b-wave amplitude associated with prolonged implicit times for both the b-wave and oscillatory potentials, and mice with 3' defects have a phenotype similar to that seen in DMD/BMD patients. The mouse studies suggest a key role for the carboxyl terminal dystrophin isoform, Dp260, in retinal electrophysiology. We have undertaken a systematic evaluation of DMD/BMD patients through clinical examination and review of the literature in order to determine whether the position-specific effects of mutations noted in the mouse are present in man. We have found that, in man, a wider variation of DMD defects correlate with reductions in the b-wave amplitude. Individuals with normal ERGs have mutations predominantly located 5' of the transcript initiation site of Dp260. Our results suggest that the most important determinant in the ERG b-wave phenotype is the mutation position, rather than muscle disease severity. Forty-six per cent of patients with mutations 5' of the Dp260 transcript start site have abnormal ERGs, as opposed to 94% with more distal mutations. The human genotype-phenotype correlations are consistent with a role for Dp260 in normal retinal electrophysiology and may also reflect the expression of other C-terminal dystrophin isoforms and their contributions to retinal signal transmission.

Hemifacial microsomia in a newborn with hypoplastic skin lesions, an eyelid skin tag, and microphthalmia: an unusual presentation of Delleman syndrome.

Delleman syndrome (oculocerebrocutaneous syndrome) is characterized by orbital cysts, periorbital skin appendages, and focal cutaneous hypoplasia. We describe a male infant with findings associated with this condition, including an eyelid appendage, discrete hypoplastic skin lesions, unilateral microphthalmia, and hydrocephalus. In addition, he had striking unilateral mandibular hypoplasia and microtia, features often present in the oculoauriculovertebral (OAV) spectrum. However, hypoplastic skin lesions and eyelid appendages are not features of the OAV spectrum. The marked degree of hemifacial microsomia present in this child has not been previously noted in Delleman syndrome. Two patients with Delleman syndrome have been previously described who have features typically present in the OAV spectrum. This case demonstrates that characteristics of both Delleman syndrome and the OAV spectrum may be present in one individual.

OA1 mutations and deletions in X-linked ocular albinism.

X-linked ocular albinism (OA1), Nettleship-Falls type, is characterized by decreased ocular pigmentation, foveal hypoplasia, nystagmus, photodysphoria, and reduced visual acuity. Affected males usually demonstrate melanin macroglobules on skin biopsy. We now report results of deletion and mutation screening of the full-length OA1 gene in 29 unrelated North American and Australian X-linked ocular albinism (OA) probands, including five with additional, nonocular phenotypic abnormalities (Schnur et al. 1994). We detected 13 intragenic gene deletions, including 3 of exon 1, 2 of exon 2, 2 of exon 4, and 6 others, which span exons 2-8. Eight new missense mutations were identified, which cluster within exons 1, 2, 3, and 6 in conserved and/or putative transmembrane domains of the protein. There was also a splice acceptor-site mutation, a nonsense mutation, a single base deletion, and a previously reported 17-bp exon 1 deletion. All patients with nonocular phenotypic abnormalities had detectable mutations. In summary, 26 (approximately 90%) of 29 probands had detectable alterations of OA1, thus confirming that OA1 is the major locus for X-linked OA.

Acute lymphoblastic leukemia in a child with the CHIME neuroectodermal dysplasia syndrome.

The "CHIME" syndrome (MIM#280000) is a rare neuroectodermal disorder comprised of Colobomas of the eye, Heart defects, Ichthyosiform dermatosis, Mental retardation, and Ear defects. We report on the sixth child with this syndrome and the first of these to develop acute lymphoblastic leukemia at age 4 1/2 years. Her major problems included a migratory ichthyosiform dermatosis, multiple skin infections and infestations, bilateral retinal coloboma, developmental delay, seizures, infantile macrosomia, facial anomalies, a duplicated renal collecting system, and conductive hearing loss. Histologic examination of the skin demonstrated findings of an epidermal nevus with deep rete pegs, hyperkeratosis, and a markedly increased granular layer. The cause of the CHIME syndrome is unknown, but the disorder is easily recognized because of the striking phenotype. The diagnosis is important to make because of the potential for associated congenital heart disease, neurologic compromise, possible autosomal recessive inheritance, and possible association with malignancy.

Magnetization transfer in the investigation of patients with tuberous sclerosis.

We examined 21 patients aged 5 months to 19 years, on a 1.5 T magnet. T1-weighted spin-echo images, proton density and T2-weighted images with spin-echo and turbo spin-echo sequences, and contrast-enhanced magnetization transfer (MT) T1-weighted images were obtained in all cases. MT T1-weighted images were performed before injection in 9 patients. Subependymal nodules were found in 14, and cortical and subcortical tubers in 20 of the 21 patients. MT T1-weighted images showed tubers and subependymal nodules as higher signal than normal gray matter and revealed more tubers than conventional sequences in 11 cases. High signal intensity lesions of the white matter were found in 19 patients but were seen only on MT images in 9 cases. When MT images both before and after injection were available, tubers and white matter lesions were more easily recognised on unenhanced MT images because of their higher contrast.

Utility of linked markers in genetic counseling: estimation of carrier risks in X-linked ocular albinism.

We apply a method proposed by Rogatko et al. [1995: Am J Med Genet 59:24-32] to estimate carrier risks using genetic linkage data. The method is illustrated for X-linked ocular albinism. Linkage data from pedigrees were combined with genome mapping data to compute carrier risks for individuals with unknown carrier status based on pedigree data alone. We considered two situations. First, a linkage map with some ambiguity in the gene order was considered. This analysis allows us to examine the effect of incomplete genetic map information on risk computations. Second, published physical and meiotic mapping information was used to derive a linkage map that could be assumed known without ambiguity. In both situations, the mean and median estimate of carrier risk differed significantly from that obtained using pedigree relationships only, in that the computed risk was significantly different from the a priori value of 0.5. The 95% CI's associated with point estimates of risk made using the known map or an map with ambiguity did not overlap in some cases. These results suggest that the risk estimate and the confidence with which a risk estimate can be imparted may depend on the genetic map and marker data used in the risk estimation procedure. We conclude that the method presented here can be used to estimate genetic risk under a variety of analytical conditions.

Reticulate hyperpigmentation.

Disorders that are characterized by a reticulate pattern of pigmentation are reviewed. Dyskeratosis congenita (DKC) is the prototype of these. In addition to reticulate hyperpigmentation, mucosal leukoplakia, bone marrow dysfunction, cytogenetic instability, and a predisposition to malignancy are characteristic of DKC. The most common pattern of inheritance is X-linked, with heterozygous females showing variable expression, most likely depending on tissue-specific patterns of random X-inactivation. Other reticulate pigmentary disorders reviewed include the Naegeli-Franceschetti-Jadassohn syndrome, X-linked reticulate pigmentary disorder, dermatopathia pigmentosa reticularis, Dowling-Degos disease, dyschromatosis, confluent and reticulated papillomatosis of Gougerot and Carteaud, reticulate acropigmentation of Kitamura, and Revescz syndrome. Diagnosis, treatment, and sometimes genetic counseling remain problematic for these entities. The pathophysiology of these disorders is unknown, but will certainly be aided greatly by the future identification of the underlying genes.

Type I oculocutaneous albinism associated with a full-length deletion of the tyrosinase gene.

Type I oculocutaneous albinism is an autosomal recessive disorder in which the biosynthesis of melanin is reduced or absent in skin, hair, and eyes because of deficient activity of tyrosinase (EC 1.14.18.1). Type I oculocutaneous albinism is caused by mutations in the tyrosinase structural gene, TYR; however, no large TYR gene deletions have been identified previously in humans. Here we report a patient with type IB oculocutaneous albinism who is a compound heterozygote for TYR allele containing a mutation that is likely to affect pre-RNA splicing and a paternally inherited allele in which the TYR gene is completely deleted, the first such allele described to date. Aside from the albinism in the proband, his phenotype and that of his normally pigmented father is otherwise normal, suggesting that this TYR deletion does not involve other functionally important contiguous genes.

Ablepharon macrostomia syndrome with associated cutis laxa: possible localization to 18q.

The ablepharon-macrostomia (AMS) and Barber-Say syndromes (BSS) are rare disorders characterized by absence of the eyelids or ectropion, macrostomia, ambiguous genitalia, abnormal ears, rudimentary nipples, and dry, redundant skin. Patients with Barber-Say syndrome also have hypertrichosis. We present a patient with a phenotype similar to AMS who has a complex rearrangement of chromosome 18, involving both an inversion and interstitial deletion. Our patient lacks the typical features of the 18q deletion syndrome. We review AMS and BSS as compared with our patient, and recognize cutis laxa as a feature shared by all. We propose that the gene(s) for this phenotype may lie on chromosome 18 in the region of the deletion or inversion breakpoints.

Mosaic loss of 15q11q13 in a patient with hypomelanosis of Ito: is there a role for the P gene?

We report a patient with mental retardation, behavioral disturbances, and pigmentary anomalies, consistent with the phenotype of hypomelanosis of Ito (HMI), and in whom cytogenetic analysis revealed mosaicism for an unbalanced translocation. His karyotype is 45, XY,-7,-15,+der(7)(7:15)t(q34:q13)/46,XY. He is therefore monosomic for 7q34 to qter and 15pter to q13 in the cells containing the translocation. The human homolog (P) of the p gene (the product of the mouse pink-eyed dilution locus) maps to 15q11q13. Loss of this locus is believed to be associated with abnormalities of pigmentation, such as the hypopigmentation seen in patients with deletions of 15q11q13, and the Prader-Willi and Angelman syndromes. Mutations within the P gene have also been associated with tyrosinase-positive (type II) oculocutaneous albinism. Using fluorescence in situ hybridization, we confirmed that our patient is deleted for one copy of a P gene probe in the cells with the unbalanced translocation, and for loci within the region critical for the Prader-Willi/Angelman syndromes. Although hypomelanosis of Ito is a heterogeneous disorder, we postulate that, in our case and potentially in others, this phenotype may result directly from the loss of specific pigmentation genes.