Limb-girdle Phenotype Research Articles

Homozygosity of a Founder Variant c.1508dupC in DOK7 Causes Congenital Myasthenia With Variable Severity.

Description of 15 patients with the same variant in DOK7 causing congenital myasthenic syndrome (CMS). Nine adult and 6 pediatric patients were studied with molecular genetic and clinical investigations. All patients were identified with the c.1508dupC variant in DOK7, of whom 13 were homozygous and 2 patients compound heterozygous. Only 2 patients had limb girdle phenotype, while all adult patients also had ptosis, ophthalmoplegia, facial weakness, as well as inspiratory stridor. Pediatric patients had severe respiratory insufficiency and feeding difficulties at birth. The disease severity in our patients varied extensively from ventilator or wheelchair dependence to mild facial weakness, ptosis, and ophthalmoparesis. Most of the patients had normal transmission in conventional 3 Hz stimulation electrophysiologic studies, making the diagnosis of CMS challenging. Our cohort of adult and pediatric patients expands the phenotype of DOK7 CMS and shows the importance of correct and early diagnosis.

Болезнь Помпе у взрослых: клинические проявления, диагноз и лечение

Pompe disease is a rare inherited lisosomal storage disease characterized by accumulation of glycogen in muscular cells due to a deficient activity of acid a-glucosidase (GAA), an enzyme which degrades lysosomal glycogen. Late-onset Pompe disease can have onset at any age and sometimes mani fests in the elderly. It presents with a predominant proximal muscle weakness (limb girdle phenotype), moderately elevated serum creatine kinase and other muscle enzymes and respiratory dysfunction mainly due to a diaphragmatic weakness. Diagnosis requires low GAA activity in dried blood spots and genetic testing. The authors present the case of late-onset Pompe disease diagnosed in 45-year old male patient and discuss the efficacy of enzyme replacement therapy with recombinant GAA.

Novel DPAGT1 Gene Mutation in Two Twins with Congenital Myasthenic Syndrome and a Review of the Literature.

Congenital myasthenic syndromes (CMS) are rare diseases caused by mutation in genes coding for proteins involved in neuromuscular junction structure and function. DPAGT1 gene mutations are a rare cause of CMS whose clinical evolution and pathophysiological mechanisms have not been clarified completely. We present the case of two twins displaying an infancy-onset predominant limb-girdle phenotype and carrying a novel DPAGT1 mutation associated with unusual histological and clinical findings. CMS can mimic paediatric and adult limb-girdle phenotype, hence neurophysiology plays a fundamental role in the differential diagnosis.

Clinical-pathological features and muscle imaging findings in 36 Chinese patients with rimmed vacuolar myopathies: case series study and review of literature.

Rimmed vacuolar myopathies (RVMs) are a group of genetically heterogeneous diseases that share histopathological characteristics on muscle biopsy, including the aberrant accumulation of autophagic vacuoles. However, the presence of non-coding sequences and structural mutations, some of which remain undetectable, confound the identification of pathogenic mutations responsible for RVMs. Therefore, we assessed the clinical profiles and muscle magnetic resonance imaging (MRI) changes in 36 Chinese patients with RVMs, emphasizing the role of muscle MRI in disease identification and differential diagnosis to propose a comprehensive literature-based imaging pattern to facilitate improved diagnostic workup. All patients presented with rimmed vacuoles with varying degrees of muscular dystrophic changes and underwent a comprehensive evaluation using clinical, morphological, muscle MRI and molecular genetic analysis. We assessed muscle changes in the Chinese RVMs and provided an overview of the RVMs, focusing on the patterns of muscle involvement on MRI. A total of 36 patients, including 24 with confirmed distal myopathy and 12 with limb-girdle phenotype, had autophagic vacuoles with RVMs. Hierarchical clustering of patients according to the predominant effect of the distal or proximal lower limbs revealed that most patients with RVMs could be distinguished. GNE myopathy was the most prevalent form of RVMs observed in this study. Moreover, MRI helped identify the causative genes in some diseases (e.g., desminopathy and hereditary myopathy with early respiratory failure) and confirmed the pathogenicity of a novel mutation (e.g., adult-onset proximal rimmed vacuolar titinopathy) detected using next-generation sequencing. Collectively, our findings expand our knowledge of the genetic spectrum of RVMs in China and suggest that muscle imaging should be an integral part of assisting genetic testing and avoiding misdiagnosis in the diagnostic workup of RVM.

A case of dysferlinopathy (Miyoshi distal myopathy limb-girdle muscular dystrophy type 2b phenotype) from a tertiary care hospital

Limb girdle muscular dystrophy type 2B (LGMD2B) and Miyoshi myopathy are caused by similar mutations in the dysferlin gene. The phenotype of these allelic disease variants can vary considerably. We report a young male with severe and rapidly progressing muscle disorder with increased creatine phosphokinase (CPK) and confirmatory muscle biopsy findings. Genetic testing was done. A homozygous nonsense variation in exon 23 of the DYSF gene, which was consistent with the patient’s clinical reports of dysferlinopathy. Clinical phenomenology and preferential muscle involvement lead one to the gold standard genetic testing in heritable myopathies, which was well established in this report.

LAMA2-Related Muscular Dystrophy: The Importance of Accurate Phenotyping and Brain Imaging in the Diagnosis of LGMD.

We report three siblings from a non-consanguineous family presenting with contractural limb-girdle phenotype with intrafamilial variability. Muscle MRI showed posterior thigh and quadriceps involvement with a sandwich-like sign. Whole-exome sequencing identified two compound heterozygous missense TTN variants and one heterozygous LAMA2 variant. Brain MRI performed because of concentration difficulties in one of the siblings evidenced white-matter abnormalities, subsequently found in the others. The genetic analysis was re-oriented, revealing a novel pathogenic intronic LAMA2 variant which confirmed the LAMA2-RD diagnosis. This work highlights the importance of a thorough clinical phenotyping and the importance of brain imaging, in order to orientate and interpret the genetic analysis.

Deep phenotyping of an international series of patients with late-onset dysferlinopathy.

To describe the clinical, pathological, and molecular characteristics of late-onset (LO) dysferlinopathy patients. Retrospective series of patients with LO dysferlinopathy, defined by an age at onset of symptoms ≥30years, from neuromuscular centers in France and the International Clinical Outcome Study for dysferlinopathy (COS). Patients with early-onset (EO) dysferlinopathy (<30years) were randomly selected from the COS study as a control group, and the North Star Assessment for Dysferlinopathy (NSAD) and Activity Limitation (ACTIVLIM) scores were used to assess functionality. Muscle biopsies obtained from 11 LO and 11 EO patients were revisited. Forty-eight patients with LO dysferlinopathy were included (28 females). Median age at onset of symptoms was 37 (range30-57) years and most patients showed a limb-girdle (n=26) or distal (n=10) phenotype. However, compared with EO dysferlinopathy patients (n=48), LO patients more frequently showed atypical phenotypes (7 vs. 1; p=0.014), including camptocormia, lower creatine kinase levels (2855 vs. 4394 U/L; p=0.01), and higher NSAD (p=0.008) and ACTIVLIM scores (p=0.016). Loss of ambulation in LO patients tended to occur later (23±4.4years after disease onset vs. 16.3±6.8years; p=0.064). Muscle biopsy of LO patients more frequently showed an atypical pattern (unspecific myopathic changes) as well as significantly less necrosis regeneration and inflammation. Although LO patients more frequently showed missense variants (39.8% vs. 23.9%; p=0.021), no differences in dysferlin protein expression were found on Western blot. Late-onset dysferlinopathy patients show a higher frequency of atypical presentations, are less severely affected, and show milder dystrophic changes in muscle biopsy.

AUTOPHAGIC MYOPATHIES / MYOFIBRILLAR MYOPATHIES / DISTAL MYOPATHIES / POMPE DISEASE: P.17 Screening for Pompe disease using muscle section in Japan

Pompe disease (PD) is an autosomal recessive glycogen storage disease due to deficiency of acid alpha-glucosidase (GAA). As enzyme replacement therapy is available, any patient should not be overlooked. However, late-onset PD (LOPD) cases can often clinically show nonspecific limb-girdle phenotype and sometimes pathologically lack pathognomonic vacuolar changes. Although we have reported acid-phosphatase-positive globular inclusion in myofibers as a diagnostic marker, still PD cases may be overlooked on routine muscle pathology diagnosis as the inclusion may not always be obvious.

The genetic profile of dysferlinopathy in a cohort of 209 cases: Genotype-phenotype relationship and a hotspot on the inner DysF domain.

Dysferlinopathy is a group of autosomal recessive muscular dystrophies caused by variants in the dysferlin gene (DYSF), with variable proximal and distal muscle involvement. We performed DYSF gene analyses of 200 cases suspected of having dysferlinopathy (Cohort 1), and identified diagnostic variants in 129/200 cases, including 19 novel variants. To achieve a comprehensive genetic profile of dysferlinopathy, we analyzed the variant data from 209 affected cases from unrelated 209 families, including 80 previously diagnosed and 129 newly diagnosed cases (Cohort 2). Among the 90 types of variants identified in 209 cases, the NM_003494.3: c.2997G>T; p.Trp999Cys, was the most frequent (96/420; 22.9%), followed by c.1566C>G; p.Tyr522* (45/420; 10.7%) on an allele base. p.Trp999Cys was found in 70/209 cases (33.5%), including 20/104 cases (19.2%) with the Miyoshi muscular phenotype and 43/82 cases (52.4%) with the limb-girdle phenotype. In the analysis of missense variants, p.Trp992Arg, p.Trp999Arg, p.Trp999Cys, p.Ser1000Phe, p.Arg1040Trp, and p.Arg1046His were located in the inner DysF domain, representing in 113/160 missense variants (70.6%). This large cohort highlighted the frequent missense variants located in the inner DysF domain as a hotspot for missense variants among our cohort of 209 cases (>95%, Japanese) and hinted at their potential as targets for future therapeutic strategies.

Congenital muscular dystrophies and congenital myopathies: A study of mutational pattern and phenotypic variability from a tertiary care hospital in India

To characterize the genetic subtypes of Congenital muscular dystrophies (CMD) and Congenital myopathies (CM). A retrospective analysis of CMD and CM (2015–2019) confirmed by exome sequencing. Institutional Ethics Committee approval obtained for the study. CMD group: 15 patients; M:F = 2:3. Onset was congenital in Ullrich CMD(UCMD), FKRP and LAMA2, adult in Bethlem myopathy(BM) and variable in LMNA. Common findings: Contractures, limb girdle and facial weakness, elevated serum creatine kinase. Calf hypertrophy in LAMA2 and FKRP. UCMD (P1,2): Recessive nonsense(p.Gln104ter, p.Gln27ter) mutations in Col6A2 and Col6A3. BM (P3-7): P3-5 had dominant missense mutations in Col6A2(p.Gly564Arg), Col6A1(p.Gly269Ar) and Col12A1(p.Gly982Arg). Co6A3 nonsense(p.Arg59ter) and c.6309+3A>G(5'splice) mutations in P6,7. LAMA2 (P8,9): Compound heterozygous mutations(p.Lys1726ter|p.Arg2604ter; p.Arg2319ter|del 34-37ex): leukoencephalopathy and cerebellar cysts on imaging. LMNA (P10-14): Onset: infancy to 3rd decade. P10-13 had heterozygous missense mutations(p.Arg453Trp, p.Leu102Pro, p.Asn39His and p.Val440Met). Variable phenotypes: P10,11: EDMD, P12: LGMD, P13: RSS with DCM. P14 with biallelic (p.Glu124Argfs*3|p.Glu124Gln) mutations: EDMD with adult progeria features. FKRP (P15): Recessive(p.Pro448Leu) mutation: limb-girdle phenotype. CM group: 12 patients; M:F = 2:1. Infantile onset with motor delay in RYR1, DES and SEPN1. Ptosis was common in all except RYR1. RYR1 (P1-4): P1&2 had opthalmoparesis: compound heterozygous(p.Leu2963Pro| p.Ser783Leu; p.Glu4464Asp|p.Arg628His) mutations. P1 biopsy showed centronuclear myopathy(CNM). P3 had heterozygous(p.Gly3288Arg) mutation. P4 with CM and bullous skin lesions: concomitant RYR1 frameshift(p.Leu108SerfsTer10) and COL7A1 5’splice(c.8620+3G>A) mutations. DES (P5,6): Recessive truncating(p.Arg150Ter, p.Glu320ArgfsTer2) mutations. Variable phenotypes: P5: CM with dilated cardiomyopathy(DCM), P6: Congenital myasthenic syndrome(CMS). SEPN1 (P7,8): Rigid spine syndrome(RSS) with homozygous(p.Met525Arg, p.Ala195Thr) mutations. DNM2 (P9,10): Onset:11-12 years with limb-girdle weakness. Dominant(p.Glu368Lys, p.Val798Met) mutations. This study highlights the mutational pattern and challenging conundrums of genotype-phenotype correlations in CMD and CM.

Progression of GNE Myopathy Based on the Patient-Reported Outcome.

Background and PurposeGNE myopathy is a rare progressive myopathy caused by biallelic mutations in the GNE gene, and frequently accompanied by rimmed vacuoles in muscle pathology. The initial symptom of foot drop or hip-girdle weakness eventually spreads to all limbs over a period of decades. Recent advances in pathophysiologic research have facilitated therapeutic trials aimed at resolving the core biochemical defect. However, there remains unsettled heterogeneity in its natural course, which confounds the analysis of therapeutic outcomes. We performed the first large-scale study of Korean patients with GNE myopathy.MethodsWe gathered the genetic and clinical profiles of 44 Korean patients with genetically confirmed GNE myopathy. The clinical progression was estimated retrospectively based on a patient-reported questionnaire on the status of the functional joint sets and daily activities.ResultsThe wrist and neck were the last joints to lose antigravity functionality irrespective of whether the weakness started from the ankle or hip. Two-thirds of the patients could walk either independently or with an aid. The order of losing daily activities could be sorted from standing to eating. Patients with limb-girdle phenotype showed an earlier age at onset than those with foot-drop onset. Patients with biallelic kinase domain mutations tended to progress more rapidly than those with epimerase and kinase domain mutations.ConclusionsThe reported data can guide the clinical management of GNE myopathy, as well as provide perspective to help the development of clinical trials.

Targeted gene panel screening is an effective tool to identify undiagnosed late onset Pompe disease

Mutations in the GAA gene may cause a late onset Pompe disease presenting with proximal weakness without the characteristic muscle pathology, and therefore a test for GAA activity is the first tier analysis in all undiagnosed patients with hyperCKemia and/or limb-girdle muscular weakness. By using MotorPlex, a targeted gene panel for next generation sequencing, we analyzed GAA and other muscle disease-genes in a large cohort of undiagnosed patients with suspected inherited skeletal muscle disorders (n = 504). In this cohort, 275 patients presented with limb-girdle phenotype and/or an isolated hyperCKemia. Mutational analysis identified GAA mutations in ten patients. Further seven affected relatives were identified by segregation studies. All the patients carried the common GAA mutation c.-32-13T >G and a second, previously reported mutation. In the subcohort of 275 patients with proximal muscle weakness and/or hyperCKemia, we identified late-onset Pompe disease in 10 patients. The clinical overlap between Pompe disease and LGMDs or other skeletal muscle disorders suggests that GAA and the genes causing a metabolic myopathy should be analyzed in all the gene panels used for testing neuromuscular patients. However, enzymatic tests are essential for the interpretation and validation of genetic results.

Pompe disease in Austria: clinical, genetic and epidemiological aspects

In this study, we performed a survey of infantile and late-onset Pompe disease (IOPD and LOPD) in Austria. Paediatric and neuromuscular centres were contacted to provide a set of anonymized clinical and genetic data of patients with IOPD and LOPD. The number of patients receiving enzyme replacement therapy (ERT) was obtained from the pharmaceutical company providing alglucosidase alfa. We found 25 patients in 24 families, 4 IOPD and 21 LOPD with a resulting prevalence of 1:350,914. The most frequent clinical manifestation in LOPD was a lower limb-girdle phenotype combined with axial weakness. Three patients were clinically pauci- or asymptomatic and were diagnosed because of persistent hyperCKemia. Diagnostic delay in LOPD was 7.4 ± 9.7 years. The most common mutation was c.-32-13T > G. All IOPD and 17 symptomatic LOPD patients are receiving ERT. Standardized follow-up was only available in six LOPD patients for the 6-min walk test (6minWT) and in ten for the forced vital capacity (FVC). Mean FVC did not decline (before ERT; 63.6 ± 39.7%; last evaluation during ERT: 61.9 ± 26.9%; P = 0.5) while there was a trend to decline in the mean distance covered by the 6minWT (before ERT: 373.5 ± 117.9 m; last evaluation during ERT: 308.5 ± 120.8 m; P = 0.077). The study shows a lower prevalence of Pompe disease in Austria than in other European countries and corroborates a limb-girdle phenotype with axial weakness as the most common clinical presentation, although asymptomatic hyperCKemia may be the first indication of LOPD.

P.472 - Unexpected gene expression findings in the titinopathy mouse model FINmaj-KI using RNA-Seq

Heterozygous dominant mutations in the C-terminal part of the sarcomeric protein titin cause tibial muscular dystrophy (TMD; OMIM: #600334). In Finland, the most common mutation is an 11-bp insertion/deletion called FINmaj and homozygosity of the FINmaj mutation cause a much more severe limb-girdle phenotype (LGMD2J; OMIM: #608807). Gene expression changes caused by this mutation have previously been studied in patient muscle biopsies already showing significant muscle pathology and the early changes caused by titin mutations were therefore beyond reach. The mouse model FINmaj-KI makes studies of pre-symptomatic changes feasible. Here, we have studied the gene expression in wild-type, heterozygous and homozygous FINmaj-KI mice at 2 months of age, before the muscle sample show any pathology, using RNA sequencing. The results indicate changes in a variety of cellular pathways including changes in genes encoding extracellular matrix proteins.

Correlation of phenotype and genotype in Croatian patients with Collagen VI (COL6) gene de novo mutations

Muscle dystrophies present very heterogenous group of muscle disorders. Objective: To present variability of phenotype in Croatian patients with collagen VI gene mutations and diagnostic significance of muscle MR imaging. Methods: Electromyography (EMG), muscle biopsy, cardiac ultrasound, whole exome sequencing (WES) and muscle MR imaging (MRI) were performed in all patients. Results: We present 6 patients from 3 families: 5 children at the age 6–14 years and 1 adult (mother of one of the patients). Clinical features of muscle weakness primarily of the limb girdle type, positive Gowers sign, and elbow, hip and finger contractures were present at the age 14 months–4 years. CK levels were normal or mildly elevated (up to 400 U/L), EMG revealed myopathic pattern. Muscle biopsy performed in 4 children revealed muscle fibers variability and increased connective tissue, while in 2 children signs of neurogenic atrophy were present as well. Whole exome sequencing (WES) confirmed COL6 mutations in all 6 patients and their parents. Diagnosis was supported by muscle MRI of the lower limbs. Two patients (mother and daughter) developed severe type of disease and wheelchair dependency at the age 40 and 15 years. Cardiac ultrasound revealed borderline cardyomyopathy in one male patient at the age of 14 years. Conclusion: COL6-related myopathy is important in differential diagnosis of patients with muscle weakness and hypotrophy of limb girdle phenotype and congenital myopathies with normal or mildly elevated CK values. They can be inherited in both recessive and dominant traits. Phenotype and muscle biopsy are often not informative or specific. Muscle MR imaging, along with WES is important in diagnosis of COL6-related myopathies, including cases with atypical clinical phenotype or in de novo COL6 gene mutations.

A limb-girdle myopathy phenotype of RUNX2 mutation in a patient with cleidocranial dysplasia: a case study and literature review

BackgroundCleidocranial dysplasia (CCD) is a rare hereditary disorder that arises from heterozygous loss of function mutations in the runt-related transcription factor 2 (RUNX2) gene. As RUNX2 is mainly expressed in osteoblasts, CCD typically affects the skeletal and dental systems. Few studies have investigated RUNX2 mutation effects on non-skeletal systems. Here, we describe limb-girdle myopathy, an uncommon phenotype of CCD, in a patient with a heterozygous missense mutation (p.R225Q) in the RUNX2 gene.Case presentationA 58 year-old man presented with progressive back pain and six months of weakness in the proximal parts of all four limbs. Physical examinations showed that he was short in stature (height, 164.4 cm; weight, 79.1 kg) with a dysmorphic face, including hypertelorism, midface hypoplasia, and chin protrusion. At a young age, he had received orthodontic surgery, due to dental abnormalities. Neurological examinations revealed sloping shoulders, weakness, and atrophy in the proximal areas of the arms, shoulder girdle muscles, and legs. The deep tendon reflex and sensory system were normal. Radiological examinations revealed mild scoliosis, shortened clavicles, and a depressed skull bone, which were consistent with a clinical diagnosis of CCD. Electromyography (EMG) studies showed myogenic polyphasic waves in the deltoid, biceps brachii, and rectus femoris muscles. Instead, the EMG findings were normal in the first dorsal interosseous, tibialis anterior and facial muscles. The EMG findings were compatible with a limb-girdle pattern with facial sparing. The patient’s family history showed his father and eldest daughter with similar dysmorphic faces, skeletal disorders and proximal upper extremity weakness. We sequenced the RUNX2 gene and discovered a heterozygous missense mutation (c.G674A, p.R225Q), which altered the C-terminal end of the RUNX2 protein. This mutation was predicted to inactivate the protein and might affect its interactions with other proteins. This mutation co-segregated with the disease phenotypes in the family.ConclusionsWe described limb-girdle myopathy in a patient with CCD that carried a heterozygous RUNX2 missense mutation. This uncommon phenotype expanded the phenotypic spectrum of the RUNX2 p.R225Q mutation. The role of RUNX2 in myogenic development merits future studies. Our findings remind clinicians that myopathic patients with myopathies combined with facial dysmorphism and shortened clavicles should consider the diagnosis of CCD.

P.255 - Severe cardiopathy in a patient with a new mutation of the fukutin gene with limb girdle phenotype

P.255 - Severe cardiopathy in a patient with a new mutation of the fukutin gene with limb girdle phenotype

Prevalence of Pompe disease in 3,076 patients with hyperCKemia and limb-girdle muscular weakness.

We prospectively screened a large European cohort of patients presenting with hyperCKemia and/or limb-girdle muscular weakness (LGMW) for acid α-glucosidase (GAA) deficiency by dried blood spot (DBS) investigation. DBS were collected from 3,076 consecutive adult patients from 7 German and British neuromuscular centers. All specimens were investigated for GAA deficiency by fluorometry. Samples with reduced enzyme activity were subsequently investigated for GAA gene mutations. Of 3,076 patients with DBS samples, 232 patients (7.6%) showed low GAA enzyme activity. Of these 232 patients, 55 (24%) presented with isolated hyperCKemia and 176 (76%) with hyperCKemia and LGMW. With both features present, 94% of the patients showed a low enzymatic activity. Mutational analysis found GAA gene mutations in 74 patients (2.4%); herein 70 patients were heterozygote for the common GAA gene splice-site mutation c.-32-13T>G. The most common clinical presentation in the confirmed Pompe cohort was a limb-girdle phenotype (85.3%) combined with ventilatory insufficiency (61%). Isolated hyperCKemia was found in 12%, while 2.7 had hyperCKemia and ventilatory insufficiency only. In a large cohort of unselected adult patients with hyperCKemia and/or LGMW, we found a prevalence of late-onset Pompe disease of 2.4%. Therefore, targeted screening of such a population should be encouraged in clinical practice.

A mitochondrial tRNAMet mutation causing developmental delay, exercise intolerance and limb girdle phenotype with onset in early childhood

A 10-year-old girl presented with exercise intolerance, learning difficulty, and muscle weakness in a limb girdle distribution. She had delayed achievement of motor milestones and difficulties with social interaction at pre-school age. Muscle biopsy showed no myopathic or dystrophic features, but 90% COX negative fibres and ragged blue fibres. Respiratory chain enzyme analysis in muscle showed a combined deficiency and mitochondrial DNA sequencing revealed the presence of an m.4450G>A mutation in the MT-TM gene encoding the tRNA for methionine. The mutation was only detected in mtDNA extracted from muscle and skin fibroblast, and could not be found in other tissues or in the mother. This is the second patient reported in the literature with a mitochondrial myopathy due to a mt-tRNAMet mutation. The first patient, a 30-year-old woman, presented with exercise intolerance, limb girdle muscle weakness, lactic acidosis, learning difficulty, and growth retardation in early childhood. Thus, the two patients exhibit strikingly overlapping phenotypes.

G.P.311: A new homozygous ISPD mutation is associated with either early limb-girdle or congenital muscular dystrophy within the same family depending on different levels of alpha-dystroglycan glycosylation

Dystroglycanopathies represent an important subgroup of recessively inherited disorders within the group of muscular dystrophies. Their severity may vary from the mild forms of adult-onset limb-girdle muscular dystrophy (LGMD), to the severe congenital muscular dystrophies with cerebral and ocular involvement. Although mutations in at least 17 genes have been identified so far, about 50% of the cases with dystroglycanopathy still remain unsolved. Recently, mutations in the isoprenoid synthase domain containing (ISPD) gene have been reported as a common cause of congenital muscular dystrophy and LGMD. We report clinical, histopathological, immunochemical, genetic and muscular MRI findings in 2 consanguineous children of Pakistani origin, carrying a new homozygous missense mutation (Gly123Arg) in the ISPD gene. Case 1 is a 8year-old female with an early limb-girdle phenotype, who lost ambulation at the age of 7.5years. Case 2 is a 2.5year-old male and second degree cousin of case 1, showing a congenital muscular dystrophy phenotype. Cognitive development, brain MRI, eye examination, electrocardiogram and echocardiogram were normal in both the patients. Western blot showed greater reduction of alpha-dystroglycan glycosylation in patient 2, and may be responsible for the greater severity of his clinical presentation. To our knowledge, this is the first report on the co-occurrence of both early limb-girdle and congenital muscular dystrophies within the same family carrying a new homozygous ISPD mutation.