The aim of this review is to evaluate the developmental, functional, and morphological aspects of the craniofacial complex in patients with myotonic dystrophy type 1 (DM1), Facioscapulohumeral muscular dystrophy (FSHD), and Duchenne muscular dystrophy (DMD). The degree of disease onset and severity varied from patient to patient, and most parameters indicated a greater degree of deterioration in older patients. It was found that all the muscular dystrophies studied showed altered craniofacial morphology, with malocclusion as the most consistent clinical characteristic. Particularly DM1 patients, who are the most studied, showed significant vertical aberration and post-normal occlusion. DMD patients are reported mainly with altered dental arch dimensions which influence functional capacities. Data for FSHD patients are very limited, but facial asymmetry and muscular weakness appear to be the most prominent findings. Patients with muscular dystrophies present deviations in growth and development as well as in orofacial morphology. Increased prevalence of malocclusions, of both skeletal and dental origins, characterize patients with muscular dystrophies. Different dentofacial characteristics are reported among patients with different types of muscular dystrophies. Further research is needed to clarify the orofacial phenotypic expression of muscular dystrophies.
Diabetic neuropathy (DN) is the least recognized complication of diabetes mellitus and may start early in the course of the disease. Aldose reductase (AKR1B1) gene promoter Z-2/Z-2 polymorphism increases the expression of AKR1B1 enzyme and may contribute to DN.We evaluated 108 Type 1 diabetes (T1D) children and adolescents (mean ± SD age: 13.5 ± 3.46 years, disease duration: 5.3 ± 3.4 years) and 150 healthy controls (age: 11.9 ± 2.7 years).In both groups, pupillary dilation (PD) in darkness, postural blood pressure test (PBPT), and vibration sensation thresholds (VST) in upper and lower limbs were estimated as indices of autonomic and peripheral neuropathy, respectively. Nerve conduction studies (NCS) were performed in patients as peripheral neuropathy index. The polymorphisms of AKR1B1 gene were evaluated using microsatellite (AC)n sequence Z.PBPT, PD, and VST impairments were more frequent in patient group compared with controls, while 38.6% of patients exhibited NCS abnormality. Gender, age, pubertal status, height, body mass index, diabetes duration, HbA1c, and anti-GAD titers were associated with neuropathy indices in patients. There was a strong correlation between PD and NCS in patients, while homozygous patients for Z-2 AKR1B1 gene polymorphism had higher prevalence of abnormal NCS (83.3% vs. 34.6%), PD (62.5% vs. 31.5%), and PBPT values compared with heterozygous or negative patients. Homozygous AKR1B1 status predicted PD, NCS, and PBPT variance, while PD, VST, NCS, and PBPT parameters accurately discriminated homozygous AKR1B1 patients.Impaired indices of peripheral and autonomic DN were present in a significant proportion of young T1D patients. PD, VST, NCS, and PBPT parameters were simultaneously associated with homozygous state of AKR1B1 Z-2 gene polymorphism, implicating polyol metabolism with both autonomic and peripheral neuropathies.
Methods: Our Department is a referral centre for DMD/BMD in Greece since 1990. Diagnosis and disease prevention is offered via prenatal diagnosis and carrier detection mainly performed with routine protocols (multiplex PCR for deletions and linkage analysis for carrier detection). During the last 10 years 415 non-related patients (400 of Greek origin and 15 Albanian) were referred for DMD/BMD testing.
Whole-Exome Sequencing (WES) has proven valuable in the characterization of underlying genetic defects in most rare diseases (RDs). Copy Number Variants (CNVs) were initially thought to escape detection. Recent technological advances enabled CNV calling from WES data with the use of accurate and highly sensitive bioinformatic tools. Amongst 920 patients referred for WES, 454 unresolved cases were further analysed using the ExomeDepth algorithm. CNVs were called, evaluated and categorized according to ACMG/ClinGen recommendations. Causative CNVs were identified in 40 patients, increasing the diagnostic yield of WES from 50.7% (466/920) to 55% (506/920). Twenty-two CNVs were available for validation and were all confirmed; of these, five were novel. Implementation of the ExomeDepth tool promoted effective identification of phenotype-relevant and/or novel CNVs. Among the advantages of calling CNVs from WES data, characterization of complex genotypes comprising both CNVs and SNVs minimizes cost and time to final diagnosis, while allowing differentiation between true or false homozygosity, as well as compound heterozygosity of variants in AR genes. The use of a specific algorithm for calling CNVs from WES data enables ancillary detection of different types of causative genetic variants, making WES a critical first-tier diagnostic test for patients with RDs.
We present molecular data from 90 Greek boys with Duchenne or Becker muscular dystrophy using cDNA analysis or multiplex PCR or both. Deletions were detected in 63.3% of patients and were mainly clustered in two areas of the gene, one in the 39 and one in the 59 end of the gene (exons 3-19 and 44-53). Almost 17% of deletion breakpoints lay in intron 44 while 29% of deletions have a breakpoint in intron 50. Thus the distribution of deletions in our DMD/BMD patients differs from that previously reported. Furthermore a 1:4.35 proximal:distal ratio was observed in familial cases and a 1:2.45 ratio in isolated ones.
Aldolase A (ALDOA), is the predominant isoform of aldolase in skeletal muscle and erythrocytes that catalyzes the reversibleconversion of fructose-1,6-bisphosphate to glyceraldehyde 3-phosphate. Autosomal recessive mutations in ALDOA, are extremely rare and cause hemolytic anemia and/or recurrent episodes of rhabdomyolysis, usually precipitated by fever. In this report we describe, clinical, laboratory and genetic data of two novel unrelated patients harboring mutations in the ALDOA gene who presented with episodic rhabdomyolysis, we review all previously published cases and discuss the most valuable features for diagnosis of this rare disorder.
Persistent hyperCKemia results from muscle dysfunction often attributed to genetic alterations of muscle-related genes, such as the dystrophin gene (DMD). Retrospective assessment of findings from DMD analysis, in association with persistent HyperCKemia, was conducted. Evaluation of medical records from 1354 unrelated cases referred during the period 1996–2021. Assessment of data concerning the detection of DMD gene rearrangements and nucleotide variants. A total of 730 individuals (657 cases, 569 of Greek and 88 of Albanian origins) were identified, allowing an overall estimation of dystrophinopathy incidence at ~1:3800 live male births. The heterogeneous spectrum of 275 distinct DMD alterations comprised exon(s) deletions/duplications, nucleotide variants, and rare events, such as chromosome translocation {t(X;20)}, contiguous gene deletions, and a fused gene involving the DMD and the DOCK8 genes. Ethnic-specific findings include a common founder variant in exon 36 (‘Hellenic’ variant). Some 50% of hyperCKemia cases were characterized as dystrophinopathies, highlighting that DMD variants may be considered the most common cause of hyperCKemia in Greece. Delineation of the broad genetic and clinical heterogeneity is fundamental for actionable public health decisions and theragnosis, as well as the establishment of guidelines addressing ethical considerations, especially related to the mild asymptomatic patient subgroup.
SCN1A, the gene encoding for the Nav1.1 channel, exhibits dominant interneuron-specific expression, whereby variants disrupting the channel’s function affect the initiation and propagation of action potentials and neuronal excitability causing various types of epilepsy. Dravet syndrome (DS), the first described clinical presentation of SCN1A channelopathy, is characterized by severe myoclonic epilepsy in infancy (SMEI). Variants’ characteristics and other genetic or epigenetic factors lead to extreme clinical heterogeneity, ranging from non-epileptic conditions to developmental and epileptic encephalopathy (DEE). This current study reports on findings from 343 patients referred by physicians in hospitals and tertiary care centers in Greece between 2017 and 2023. Positive family history for specific neurologic disorders was disclosed in 89 cases and the one common clinical feature was the onset of seizures, at a mean age of 17 months (range from birth to 15 years old). Most patients were specifically referred for SCN1A investigation (Sanger Sequencing and MLPA) and only five for next generation sequencing. Twenty-six SCN1A variants were detected, including nine novel causative variants (c.4567A>Τ, c.5564C>A, c.2176+2T>C, c.3646G>C, c.4331C>A, c.1130_1131delGAinsAC, c.1574_1580delCTGAGGA, c.4620A>G and c.5462A>C), and are herein presented, along with subsequent genotype–phenotype associations. The identification of novel variants complements SCN1A databases extending our expertise on genetic counseling and patient and family management including gene-based personalized interventions.
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