Observation of novel COX20 mutations related to autosomal recessive axonal neuropathy and static encephalopathy.

Cytochrome c oxidase 20 (COX20)/FAM36A encodes a conserved protein that is important for the assembly of COX, complex IV of the mitochondrial respiratory chain. A homozygous mutation (p.Thr52Pro) in COX20 gene has been previously described to cause muscle hypotonia and ataxia. In this study, we describe two patients from a non-consanguineous family exhibiting autosomal recessive sensory-dominant axonal neuropathy and static encephalopathy. The whole-exome sequencing analysis revealed that both patients harbored compound heterozygous mutations (p.Lys14Arg and p.Trp74Cys) of COX20 gene. The pathogenicity of the variants was further supported by morphological alternations of mitochondria observed in sural nerve and decreased COX20 protein level of peripheral blood leucocytes derived from the patients. In conclusion, COX20 might be considered as a candidate gene for the complex inherited disease. This observation broadens the clinical and genetic spectrum of COX20-related disease. However, due to the limitation of a single-family study, additional cases and studies are definitely needed to further confirm the association.

X-Linked Hereditary Motor Sensory Neuropathy Type 1 (CMTX1) in a Three-Generation Gelao Chinese Family.

In this report, we describe a three-generation family (the Gelao nationality, a minority ethnic group from Guizhou Province in the southwest China) with one affected member with Charcot-Marie-Tooth neuropathy X type 1 (CMTX1) in each generation. The three affected members carrying the R164W mutation in the Cx32 gene had different clinical symptoms. The proband, a 13-year-old boy presented recurrent episodes of transient central nervous system symptoms and concomitant transient diffuse white matter lesions on magnetic resonance imaging. His grandfather had the peripheral neurological presentations with later onset in the fourth decade, characterized by slowly progressive weakness of the distal muscles, atrophy, and foot deformities. But no sensory loss was observed. The proband's 38-year-old mother denied any neurological symptoms. The examination was normal except for pes cavus and diminished deep tendon reflexes in her lower limbs bilaterally. Genetic sequencing revealed the proband and his grandfather had a hemizygous mutation (p.164R > W) of CJB1 gene, and his mother had R164W heterozygous mutation. Our three cases denied symptoms of sensory disturbances, the sensory examination including touch, pin prick, and temperature sensation showed no obvious abnormalities. Thus, further investigation is needed to improve our understanding of the Cx32 protein function in the nervous system.

The spectrum of foot deformities in Loeys-Dietz syndrome.

Loeys-Dietz syndrome (LDS) is characterized by a wide spectrum of musculoskeletal manifestations, including foot deformities. The spectrum of foot deformities in LDS has not been previously characterized. Our objective was to describe the incidence and characteristics of foot deformities in LDS. We retrospectively reviewed the demographic, clinical and imaging data for patients diagnosed with LDS who were seen at our Orthopedic surgery department from 2008 to 2021. We performed descriptive analyses and compared distributions of deformities by LDS genetic mutations. Of the 120 patients studied, most presented for evaluation of foot deformities ( N = 56, 47%) and scoliosis ( N = 45; 38%). Ninety-seven patients (81%) had at least one foot deformity, and 87% of these patients had bilateral foot deformities. The most common deformities were pes planovalgus (53%) and talipes equinovarus (34%). Of patients with foot deformities, 58% presented for evaluation of the feet. Of patients with pes planovalgus, only 17% presented for evaluation of the feet. Among patients with pes planovalgus, 2% underwent surgery and 16% used orthotics compared with 76% and 42%, respectively, for patients with talipes equinovarus. We found no association between deformities and genetic mutations. Bilateral foot deformities are highly prevalent in patients with LDS and are the most common reason for presentation to orthopedic surgeons. Although pes planovalgus is the most common deformity, it rarely prompted surgical treatment. Orthopedic surgeons treating LDS patients should be aware of the unique characteristics of foot deformities in LDS.

Distinctive genetic and clinical features of CMT4J: a severe neuropathy caused by mutations in the PI(3,5)P2 phosphatase FIG4.

Charcot-Marie-Tooth disease is a genetically heterogeneous group of motor and sensory neuropathies associated with mutations in more than 30 genes. Charcot-Marie-Tooth disease type 4J (OMIM 611228) is a recessive, potentially severe form of the disease caused by mutations of the lipid phosphatase FIG4. We provide a more complete view of the features of this disorder by describing 11 previously unreported patients with Charcot-Marie-Tooth disease type 4J. Three patients were identified from a small cohort selected for screening because of their early onset disease and progressive proximal as well as distal weakness. Eight patients were identified by large-scale exon sequencing of an unselected group of 4000 patients with Charcot-Marie-Tooth disease. In addition, 34 new FIG4 variants were detected. Ten of the new CMT4J cases have the compound heterozygous genotype FIG4(I41T/null) described in the original four families, while one has the novel genotype FIG4(L17P/nul)(l). The population frequency of the I41T allele was found to be 0.001 by genotyping 5769 Northern European controls. Thirty four new variants of FIG4 were identified. The severity of Charcot-Marie-Tooth disease type 4J ranges from mild clinical signs to severe disability requiring the use of a wheelchair. Both mild and severe forms have been seen in patients with the same genotype. The results demonstrate that Charcot-Marie-Tooth disease type 4J is characterized by highly variable onset and severity, proximal as well as distal and asymmetric muscle weakness, electromyography demonstrating denervation in proximal and distal muscles, and frequent progression to severe amyotrophy. FIG4 mutations should be considered in Charcot-Marie-Tooth patients with these characteristics, especially if found in combination with sporadic or recessive inheritance, childhood onset and a phase of rapid progression.

Phenotypic heterogeneity and mosaicism in Xia-Gibbs syndrome: Five Danish patients with novel variants in AHDC1.

Xia-Gibbs syndrome (XGS) is a neurodevelopmental disorder characterized by intellectual disability, developmental delay, seizures, hypotonia, obstructive sleep apnoea and mild facial dysmorphism. Heterozygosity for loss-of-function variants in AHDC1, encoding the AT-hook DNA binding motif containing protein 1, were discovered in 2014 as the likely genetic cause of Xia-Gibbs syndrome. We present five patients with Xia-Gibbs syndrome caused by previously unreported variants in AHDC1. Two of the patients share a frameshift variant: c.2849del (p.(Pro950Argfs*192)) in AHDC1. Despite sharing this variant, the two patients show remarkable phenotypic differences underscoring the clinical heterogeneity of Xia-Gibbs syndrome. In addition, we present a case of Xia-Gibbs syndrome caused by mosaicism for an AHDC1 variant.

Pathogenic variants causing ABL1 malformation syndrome cluster in a myristoyl-binding pocket and increase tyrosine kinase activity.

ABL1 is a proto-oncogene encoding a nonreceptor tyrosine kinase, best known in the somatic BCR-ABL fusion gene associated with chronic myeloid leukaemia. Recently, germline missense variants in ABL1 have been found to cause an autosomal dominant developmental syndrome with congenital heart disease, skeletal malformations and characteristic facies. Here, we describe a series of six new unrelated individuals with heterozygous missense variants in ABL1 (including four novel variants) identified via whole exome sequencing. All the affected individuals in this series recapitulate the phenotype of the ABL1 developmental syndrome and additionally we affirm that hearing impairment is a common feature of the condition. Four of the variants cluster in the myristoyl-binding pocket of ABL1, a region critical for auto-inhibitory regulation of the kinase domain. Bio-informatic analysis of transcript-wide conservation and germline/somatic variation reveals that this pocket region is subject to high missense constraint and evolutionary conservation. Functional work to investigate ABL1 kinase activity in vitro by transient transfection of HEK293T cells with variant ABL1 plasmid constructs revealed increased phosphorylation of ABL1-specific substrates compared to wild-type. The increased tyrosine kinase activity was suppressed by imatinib treatment. This case series of six new patients with germline heterozygous ABL1 missense variants further delineates the phenotypic spectrum of this condition and recognises microcephaly as a common finding. Our analysis supports an ABL1 gain-of-function mechanism due to loss of auto-inhibition, and demonstrates the potential for pharmacological inhibition using imatinib.

The claw paw mutation reveals a role for Lgi4 in peripheral nerve development.

Peripheral nerve development results from multiple cellular interactions between axons, Schwann cells and the surrounding mesenchymal tissue. The delayed axonal sorting and hypomyelination throughout the peripheral nervous system of claw paw (clp) mutant mice suggest that the clp gene product is critical for these interactions. Here we identify the clp mutation as a 225-bp insertion in the Lgi4 gene. Lgi4 encodes a secreted and glycosylated leucine-rich repeat protein and is expressed in Schwann cells. The clp mutation affects Lgi4 mRNA splicing, resulting in a mutant protein that is retained in the cell. Additionally, siRNA-mediated downregulation of Lgi4 in wild-type neuron-Schwann cell cocultures inhibits myelination, whereas exogenous Lgi4 restores myelination in clp/clp cultures. Thus, the abnormalities observed in clp mice are attributable to the loss of Lgi4 function, and they identify Lgi4 as a new component of Schwann cell signaling pathway(s) that controls axon segregation and myelin formation.

The association of split hand foot malformation (SHFM) and congenital heart defects.

BACKGROUND: Split hand foot malformation (SHFM) (cleft hand, central ray deficiency) is a highly variable malformation that shows genetic heterogeneity with at least five loci mapped to date. SHFM occurs as an isolated finding or in association with other anomalies, including congenital heart defects (CHDs). METHODS: In total 48 SHFM1, 52 SHFM3, 48 SHFM4, 21 SHFM5, and four chromosome 8 patients were evaluated. In addition, we performed a literature review to identify "unmapped" SHFM patients with CHD to evaluate the various etiologies of this combination of findings. The London Dysmorphology Database also served as a resource to identify syndromes with this combination of phenotypic findings. Only patients presenting with both SHFM and CHD were included in the analysis. Classification of CHD among mapped and unmapped SHFM patients was performed utilizing the revised Clark classification. A closer inspection of the types of CHD found in this patient group was performed in order to investigate possible pathogenetic mechanisms. RESULTS: CHDs were found in 10% of SHFM1 patients, 47% of SHFM5 patients, but were not reported in SHFM2, SHFM4 patients, or patients mapped to chromosome 8. Forty-two syndromic cases and 15 cases of unrecognized syndromes were identified. CONCLUSIONS: The higher frequency of heart defects seen in SHFM1 and SHFM5 of the mapped patient group raises the question as to whether common mechanisms/genetic players are involved. Candidate genes for SHFM1 and SHFM5 include members of the DLX homeobox gene family.

Charcot-Marie-Tooth disease and the cavovarus foot.

This article focuses on the cavovarus foot shape, with particular emphasis on those patients who have Charcot-Marie-Tooth disease. Recent greater understanding of this deformity has led to a better appreciation of how the underlying condition drives deformity progression and treatment of the problems associated with it. The basic science underpinning the development of Charcot-Marie-Tooth disease is reviewed and some elements of the importance of the genetic variability are emphasized. The mechanics of the development of the cavovarus foot deformity in patients who have this neuromuscular condition are reviewed and the evaluation of such patients is described. The surgical options for treatment are reviewed and the outcomes of studies relevant to surgical planning for this patient population are summarized.

ZNF462 and KLF12 are disrupted by a de novo translocation in a patient with syndromic intellectual disability and autism spectrum disorder.

We describe a patient with a de novo balanced translocation 46,XY,t(9; 13)(q31.2; q22.1) and autism spectrum disorder, intellectual disability, a metopic craniosynostosis, a corpus callosum dysgenesis and dysmorphic facial features, most notably ptosis. Breakpoint mapping was performed by means of targeted locus amplification (TLA) and sequencing, because conventional breakpoint mapping by means of fluorescent in situ hybridization and long-range PCR was hampered by a complex submicroscopic rearrangement. The translocation breakpoints directly affected the genes KLF12 (chromosome 13) and ZNF462 (chromosome 9). The latter gene was disrupted by multiple breakpoints, resulting in the loss of three fragments and a rearrangement of the remaining fragments. Therefore, haploinsufficiency of ZNF462 was assumed. Loss-of-function variants in ZNF462 have recently been published by Weiss et al. (2017) in a series of eight patients from six independent families delineating the ZNF462-associated phenotype. The latter closely matches with the clinical features of the current translocation patient. Besides, no direct evidence for an association of KLF12 to the phenotypic features was found. Therefore, we conclude that the phenotype of the current patient is mainly caused by the disruption of ZNF462. We present clinical data from birth to adulthood and data on the cognitive and behavioral profile of the current patient which may add to a more precise counseling and surveillance of development in young children with ZNF462 mutations. In addition, the current case illustrates that TLA is an efficient method for determining complex chromosomal breakpoints.

Two novel variants in CNTNAP1 in two siblings presenting with congenital hypotonia and hypomyelinating neuropathy.

Homozygous frameshift variants in CNTNAP1 have recently been reported in patients with arthrogryposis and abnormal axon myelination. In two brothers with severe congenital hypotonia and foot deformities, we identified compound heterozygous variants in CNTNAP1, reporting the first causative missense variant, p.(Cys323Arg). Motor nerve conductions were markedly decreased. Nerve microscopical lesions confirmed a severe hypomyelinating process and showed loss of attachment sites of the myelin loops on the axons, which could be a characteristic of Caspr loss-of-function. We discuss the pathophysiology of the myelination process and we propose to consider this disorder as a congenital hypomyelinating neuropathy.

Difficult and controversial pediatric cases: a roundtable on conservative and surgical management.

Pediatric clinical management is highly specialized. Problems are complex and often complicated by other medical issues that dictate limitations on therapeutic options. Appropriate diagnosis and successful clinical management depend on the experience and skill of the surgeon. This roundtable discussion focuses on seven difficult cases and presents the views of three experienced and skilled experts in the field.

Identification of a de novo DYNC1H1 mutation via WES according to published guidelines.

De novo mutations that contribute to rare Mendelian diseases, including neurological disorders, have been recently identified. Whole-exome sequencing (WES) has become a powerful tool for the identification of inherited and de novo mutations in Mendelian diseases. Two important guidelines were recently published regarding the investigation of causality of sequence variant in human disease and the interpretation of novel variants identified in human genome sequences. In this study, a family with supposed movement disorders was sequenced via WES (including the proband and her unaffected parents), and a standard investigation and interpretation of the identified variants was performed according to the published guidelines. We identified a novel de novo mutation (c.2327C > T, p.P776L) in DYNC1H1 gene and confirmed that it was the causal variant. The phenotype of the affected twins included delayed motor milestones, pes cavus, lower limb weakness and atrophy, and a waddling gait. Electromyographic (EMG) recordings revealed typical signs of chronic denervation. Our study demonstrates the power of WES to discover the de novo mutations associated with a neurological disease on the whole exome scale, and guidelines to conduct WES studies and interpret of identified variants are a preferable option for the exploration of the pathogenesis of rare neurological disorders.

Peripheral neuropathy: the importance of history and examination for correct diagnosis.

A 48-year-old woman presented to the emergency department with hematemesis and a 6-month history of unsteady gait and falls due to tripping. Because of a history of alcohol abuse, the initial diagnosis was upper gastrointestinal bleeding secondary to alcoholic gastritis or gastric ulcer, with the neuropathy likely due to alcoholism or chronic inflammatory demyelinating polyneuropathy. After further neurological examination and careful review of nerve conduction studies, however, an inherited neuropathy was suspected. Despite denial by the patient and her daughter of a family history of neuropathy, both had a pes cavus deformity with muscle atrophy and partial foot drop gait. Subsequent testing of the daughter revealed the same nerve conduction findings as the patient's. Genetic testing showed that both women had the myelin PMP22 repeat defect characteristic of Charcot-Marie-Tooth disease. Endoscopy revealed that the patient had Osler-Weber-Rendu disease, which accounted for the hematemesis.

A simple method for characterising syndactyly in clinical practice.

Non-syndromic syndactyly is a heterogeneous group of limb malformations involving webbing of fingers and/or toes. There are at least nine non-syndromic types described in the literature. For the clinician and the genetic counsellor not having gathered experience with this malformation, it is rather tedious to identify the correct subtype for the patient's phenotype. We therefore present a protocol for clinical use, which visualises the malformation in a graphical way and thereby simplifies typing. In addition, this protocol provides a simple documentation system for reporting clinical data for new syndactyly families. It might encourage clinicians to report families that are still unclassifed and thus, helping to extend and improve the existing classification system.

Chromosomal localisation of a developmental gene in man: direct DNA analysis demonstrates that Greig cephalopolysyndactyly maps to 7p13.

Greig cephalopolysyndactyly syndrome (GCPS) is a rare autosomal dominant form of complex polydactyly. GCPS has been tentatively assigned to chromosome 7 on the basis of association of the condition with balanced translocations involving the short arm of chromosome 7 (7p13) in two families. Seven GCPS pedigrees with no chromosome abnormality were studied, and linkage was demonstrated between GCPS and the DNA sequence coding for the receptor for epidermal growth factor (localised to 7p12-13) (Z = 3.17; O = theta).

Prader-Willi habitus, osteopenia, and camptodactyly (Urban-Rogers-Meyer syndrome): a probable second report.

Here we describe a 12-year-old boy with finger and toe contractures, obesity, mental retardation, osteoporosis, and genital anomalies. This clinical picture was first described by Urban et al. [1979] and has been designated as "Prader-Willi habitus, osteoporosis, and hand contractures." To our knowledge, our patient represents the second report of this condition.

Greig cephalopolysyndactyly syndrome: a possible mouse homologue (Xt-extra toes).

Greig cephalopolysyndactyly syndrome is an autosomal dominant form of complex polydactyly in man. Attention is called to the evidence that, on both morphological and comparative gene mapping grounds, this defect is homologous to Xt-extra toes in the mouse. The pattern of polydactyly in both species is very similar. In addition, both conditions probably map close to the T-cell receptor gamma polypeptide at 13 A2-3 in mouse and 7p15 in humans.

New case of the Carey-Fineman-Ziter syndrome.

We present a further case, the fourth known to us, of the Carey-Fineman-Ziter syndrome. The emergence of a consistent and recognisable phenotype, characterised by hypotonia, weakness, ophthalmoplegia, and a Möbius-like clinical picture, is emphasised.