Clinical and molecular analysis of nine fetal cases with clinically significant variants causing nemaline myopathy.

OBJECTIVE: To present the prenatal features and postnatal outcomes of pregnancies with fetal nemaline myopathy (NM). STUDY DESIGN: This was a retrospective study of nine cases with NM diagnosed by prenatal or postnatal clinical features and confirmed by genetic testing. Clinical and laboratory data were collected and reviewed for these cases, including maternal demographics, prenatal sonographic findings, exome sequencing (ES) results, and pregnancy outcomes. RESULTS: All of the nine cases were detected to have NM-causing variants, involving NEB gene in 2 cases, ACTA1 in 3 cases, KLHL40 in 3 cases, and TPM2 in 1 case. Almost all (8/9) had normal first-trimester ultrasound scans except one who had an increased nuchal translucency. Seven (7/9) cases had second-trimester abnormal ultrasounds with fetal akinesia and/or extremity anomalies. Two (2/9) had only third-trimester abnormal ultrasounds with fetal akinesia and polyhydramnios, with one combined with fetal growth restriction. Four pregnancies with a positive prenatal ES were terminated, while five having not receiving prenatal ES continued to term. Only one infant survived 1 year old, and four passed away within 12 months. CONCLUSION: Prenatal ultrasound can detect clues that lead to the diagnosis of NM, such as reduced or absent fetal movements, polyhydramnios and extremity anomalies.

Muscle magnetic resonance imaging involvement patterns in nemaline myopathies.

OBJECTIVE: Characterise the diagnostic and prognostic value of muscle MRI patterns as biomarkers in a genetically heterogeneous nemaline myopathy (NM) patient cohort. METHODS: Modified Mercuri scoring of lower limb MRI in genetically characterised NM patients referred to the highly specialised service for congenital myopathies at Great Ormond Street Hospital. Findings were compared to clinical data and MRI patterns derived from collated published data. RESULTS: Twenty-seven patients with MRI were identified (8 NEB-NM, 13 ACTA1-NM, 6 TPM3-NM). NEB-NM demonstrated sparing of the thigh. ACTA1-NM demonstrated diffuse thigh involvement, notable in the vasti, sartorius and biceps-femoris, with relative adductor and gracilis sparing. TPM3-NM demonstrated diffuse thigh involvement notable in biceps-femoris and adductor magnus with relative rectus femoris, adductor longus and gracilis sparing. In the lower leg, the soleus and tibialis anterior are notably involved in all three genotypes. NEB-NM and ACTA1-NM demonstrated relative gastrocnemii and tibialis posterior sparing, while TPM3-NM showed significantly more tibialis posterior involvement (P =< 0.05). Comparison of involvement patterns with literature datasets highlighted preferential adductor and gracilis sparing in our ACTA1-NM cohort, consistent tibialis posterior involvement in our TPM3-NM cohort and a distinct MRI pattern from those derived from other NM genotypes and congenital myopathies. Greater tibialis anterior involvement correlated with foot drop (P = 0.02). Greater tibialis anterior and extensor hallucis longus involvement correlated with worse mobility (P =< 0.04). INTERPRETATION: This is the widest NM MRI data set described to date; we describe distinct muscle involvement patterns for NEB-NM, ACTA1-NM and TPM3-NM which may have utility as diagnostic and prognostic biomarkers and aid in genetic variant interpretation.

ADSSL1 myopathy is the most common nemaline myopathy in Japan with variable clinical features.

OBJECTIVE: To elucidate the prevalence of Japanese ADSSL1 myopathy and determine the clinicopathologic features of the disease. METHODS: We searched for ADSSL1 variants in myopathic patients from January 1978 to March 2019 in our repository and assessed the clinicopathologic features of patients with variants. RESULTS: We identified 63 patients from 59 families with biallelic variants of ADSSL1. Among the 7 distinct variants identified, c.781G>A and c.919delA accounted for 53.2% and 40.5% of alleles, respectively, suggesting the presence of common founders, while the other 5 were novel. Most of the identified patients displayed more variable muscle symptoms, including symptoms in the proximal and/or distal leg muscles, tongue, masseter, diaphragm, and paraspinal muscles, in adolescence than previously reported patients. Dysphagia with masticatory dysfunction developed in 26 out of 63 patients; hypertrophic cardiomyopathy developed in 12 out of 48 patients; and restrictive ventilatory insufficiency developed in 26 out of 34 patients in later stages. Radiologically, fat infiltration into the periphery of vastus lateralis, gastrocnemius, and soleus muscles was observed in all patients. Pathologically, nemaline bodies in addition to increased lipid droplets and myofibrillar disorganization were commonly observed in all patients, suggesting that the disease may be classified as nemaline myopathy. This finding revealed that ADSSL1 myopathy is the most frequent among all genetically diagnosable nemaline myopathies in our center. CONCLUSIONS: ADSSL1 myopathy is characterized by more variable manifestations than previously reported. It is the most common among all genetically diagnosable nemaline myopathies in our center, although mildly increased lipid droplets are also constantly observed features.

A family with nemaline myopathy type 6 caused by hseterozygous mutation (c.1222C>T) in the KBTBD13 gene in China: A case report.

Nemaline myopathy (NEM) is a congenital myopathy that typically presents with proximal muscle weakness and hypotonia. To date, 13 genes have been associated with NEM. The Kelch repeat and BTB domain-containing protein 13 (KBTBD13) gene (KBTBD13)-related NEM is a rarely reported condition, and not a single case has been reported in Asia. Here, we report the case of a mother and daughter in China with NEM caused by a mutation (c.1222C>T) in KBTBD13. Their shared clinical phenotype is symmetrical muscle weakness in the arms and legs with childhood onset. Muscle magnetic resonance imaging showed the unique replacement mode of muscle with fibro-fatty tissue. Histopathological examination revealed the presence of fibers containing rod-shaped structures in the cytoplasm or under the sarcolemma. DNA sequencing analysis detected a heterozygous mutation (c.1222C>T) in KBTBD13 in this family. A founder effect for the variant may exist in the Low Countries of Belgium and the Netherlands, and the mutation may be a hotspot mutation in Europe, as it has not been reported in Asia. Our case study expands the spectrum of KBTBD13-related NEM.

Camptocormia as the presenting symptom in sporadic late onset nemaline myopathy: a case report.

BACKGROUND: Camptocormia has been reported in a plethora of diseases comprising disorders of the central nervous system, the peripheral nervous system, and the neuromuscular junction as well as hereditary and acquired myopathies. In sporadic late onset nemaline myopathy concomitant axial myopathy is common, but reports about camptocormia as the only presenting symptom in this condition are very rare. Notably, sporadic late onset nemaline myopathy is a potentially treatable condition in particular when associated with monoclonal gammopathy of unknown significance, HIV or rheumatological disorders. CASE PRESENTATION: We report the case of a 62-year-old female patient, who presented with slowly progressive camptocormia. Comprehensive work-up including neurological work-up, laboratory tests, MR-imaging, muscle biopsy and genetic testing led to the diagnosis of sporadic late onset nemaline myopathy. CONCLUSIONS: Our case report highlights that sporadic late onset nemaline myopathy has to be considered in patients presenting with isolated camptocormia and comprehensive work-up of camptocormia is mandatory to ascertain the individual diagnosis, especially in consideration of treatable conditions.

LMOD3-Associated Nemaline Myopathy: Prenatal Ultrasonographic, Pathologic, and Molecular Findings.

To describe the prenatal presentation, including ultrasonographic, histologic, and molecular findings, in 2 fetuses affected with LMOD3-related nemaline myopathy. Prenatal ultrasonographic examinations and histopathologic studies were performed on 2 fetuses with evidence of nemaline myopathy. To establish a molecular diagnosis, whole-exome sequencing was pursued for the affected fetuses. Nemaline myopathy is a common form of congenital myopathy manifesting with nonprogressive generalized muscle weakness, hypotonia, and electron-dense protein inclusions in skeletal myofibers. Although clinically, nemaline myopathy can be viewed as a common pathway phenotype, its molecular basis is heterogeneous, with mutations in 11 identified genes implicated in its pathogenesis so far. Whole-exome sequencing revealed that the affected fetuses were compound heterozygous for 2 newly reported pathogenic variants in the LMOD3 gene, which encodes leiomodin 3. To our knowledge, this article is the first report of LMOD3-related nemaline myopathy since the original reported cohort. We provide a detailed description of the prenatal imaging of these affected fetuses, which we hope, in combination with next-generation sequencing, may contribute to further diagnosis in additional families.

Sporadic late-onset nemaline myopathy: clinical, pathology and imaging findings in a single center cohort.

Sporadic late-onset nemaline myopathy (SLONM) is a rare acquired myopathy characterized by rapid-onset proximal weakness in late adulthood, and the presence of nemaline bodies on muscle biopsy. In recent years, several therapeutic interventions, including immunomodulating agents and autologous stem cell transplantation, have shown variable degrees of efficacy in different patients, but no consensus has been reached to allow an effective tailoring of treatments in this severe disease. We performed a retrospective evaluation of clinical, pathological, laboratory, muscle MRI, and follow-up data of SLONM patients diagnosed in the period 2010-2015 in our neuromuscular center. Six patients (three males and three females) were identified. Average time elapsed from the onset of symptoms to referral to the neuromuscular specialist was 23.7 months. Monoclonal gammopathy was detectable in five patients. Nemaline bodies were detected in all the patients, and their abundance correlated with clinical severity. Signs of cardiac involvement were present in all the patients to different extents. Muscle MRI showed a preferential involvement of neck extensors, paraspinal, gluteal, hamstring and soleus muscles. All patients were treated with prednisone and repeated courses of intravenous immunoglobulins, and a favorable outcome was reached in five patients. Our experience confirms that SLONM is clinically characterized by subacute proximal and axial muscle weakness. Time to referral was relatively long and should be reduced with increasing awareness of the disease. Muscle MRI could be of help as a diagnostic tool to identify this potentially treatable myopathy. Cardiac evaluation should be warranted in all SLONM patients to detect subclinical heart involvement.

Clinical and genetic diversity of nemaline myopathy from a single neuromuscular center in Korea.

Nemaline myopathy (NM), the most common of the congenital myopathies, is caused by various genetic mutations. In this study, we attempted to identify the causative mutations of NM and to reveal any specific genotype-phenotype relationship in Korean patients with this disease. We investigated the clinical features and genotypes in 15 pathologically diagnosed NM patients, using whole exome sequencing (WES) combined with targeted sequencing and array-based comparative genomic hybridization. This strategy revealed pathogenic causative mutations in seven patients (46.7%), among whom mutations in the nebulin gene (NEB) were the most frequent (5 patients, 33.3%). Copy number variation (CNV) abnormality in NEB was not observed in any of our patients. In those with NEB-associated NM, the clinical spectrum was highly variable regardless of the mutation type. However, the majority of patients showing anterior lower leg weakness were associated with mutations located between NEB exons 166 and 177. We concluded that the combination of WES and targeted Sanger sequencing is an effective strategy for analyzing genotypes in patients with NM, and that CNV in NEB may not be a frequent cause of this disease among Koreans.

Miopatía de depósito de nemalina y artrogriposis congénita / Nemaline myopathy and congenital arthrogryposis

La artrogriposis es un síndrome complejo, que responde etiológicamente a numerosas causas congénitas y adquiridas. Presentamos un caso familiar de artrogriposis. La necropsia aportó el hallazgo de inclusiones rojo-púrpura en el sarcoplasma del tejido muscular, sugestiva de miopatía por nemalinas

Arthrogryposis is a complex syndrome, the aetiology of which can be traced to numerous congenital and acquired causes. We present a case of familiar arthrogryposis. Necropsy revealed red-purple rod-like structures in the sarcoplasm of the muscle tissue, suggestive of nemaline myopathy

Clinical, histological and radiological responses to methylprednisolone in HIV-associated rod myopathy.

Skeletal muscle involvement as a neurologic manifestation in individuals with HIV is rare, especially as rod myopathy. We describe a 41-year-old male with HIV infection who presented progressive proximal muscle weakness and limb-girdle atrophy. A muscle magnetic resonance image showed bilateral fatty infiltration and post-contrast enhancement in the arm and thigh muscles. The muscle biopsy revealed intracytoplasmic aggregates with appearance of nemaline rod bodies with Gomori trichrome staining and electron microscopy in most fibers. The patient underwent six cycles of intravenous methylprednisolone pulses, presenting clinical improvement. Post-treatment muscle biopsy showed fewer nemaline bodies and muscle magnetic resonance image depicted a pronounced reduction of muscular edema. These findings corroborate that deposition of nemaline bodies in these patients might be related to an immune response triggered by the virus.

Carrier state for the nebulin exon 55 deletion and abnormal prenatal ultrasound findings as potential signs of nemaline myopathy.

OBJECTIVE: To increase awareness to the possibility of nemaline myopathy (NM) when abnormal prenatal ultrasound findings appear together with a carrier state for the common exon 55 deletion in the nebulin gene (NEB) of an Ashkenazi Jewish parent. METHODS: We describe four unrelated pregnancies with abnormal prenatal ultrasound findings resulting in the birth of newborns with NM, where one or both parents were of Ashkenazi Jewish origin. Data was collected retrospectively from the patients' medical files. Molecular analysis of NEB was performed on the DNA from the patients and parents. RESULTS: Prenatal ultrasound findings included polyhydramnios, decreased fetal movements, club feet, and arthrogryposis. A biopsy from two of the newborns was consistent with NM. In all of the newborns, the common NEB exon 55 deletion was detected in the heterozygote state and in three of them, a second novel mutation was found. CONCLUSIONS: Ultrasonographic findings suggestive of a myopathy and a carrier state for the NEB exon 55 deletion in one of the parents should trigger a thorough investigation for NM. The extreme size of NEB imposes great difficulties when searching for a second mutation, especially under the time constraints of an ongoing pregnancy.

Decreased fetal movement prompts investigation of prenatal/neonatal nemaline myopathy: the possible merit of fetal movement count.

We highlight the merit of fetal movement count to identify a fetus with neuromuscular disorder: nemaline myopathy. A 38-year-old 1-para woman not in a consanguineous marriage had decreased fetal movement. This, together with increased amniotic fluid volume, led us to perform detailed ultrasound examinations, which revealed stretch contracture of the knee joints, leading us to suspect fetal neuromuscular disorders. At 38(2/7), she gave birth vaginally to a 2444 g female infant. Her respiration was very weak, requiring respiratory support. Contractures of the upper/lower extremity joints and club feet were observed. All skeletal muscles were hypotonic. Biopsized muscle cells showed nemaline bodies, confirming the diagnosis of nemaline myopathy. Fetal movement count may contribute to the identification of fetal neuromuscular diseases, such as nemaline myopathy.

[Two cases of nemaline myopathy diagnosed after episodes of respiratory failure].

Here we report two cases of congenital myopathy visited our hospital with respiratory failure. Case 1 was a 31-year-old woman, who had muscular weakness from birth but had never been diagnosed. She had an onset of pneumonia followed by severe type 2 respiratory failure. Even after the healing of pneumonia, hypercapnia remained. A diagnosis of nemaline myopathy was made after muscle biopsy. Case 2 is a 62-year-old man, who had slowly progressing respiratory failure accompanied with severe hypercapnea. His respiratory failure was improved by NIPPV. He also under went muscle biopsy and nemaline myopathy was diagnosed. Nemaline myopathy is one of congenital myopathy and is known to be a nonprogressive or slowly progressive disorder. However, some patients are diagnosed appropriately only when adult onset acute respiratory failure occurs.

[Two adult cases of nemaline myopathy presenting different clinical symptoms and CT findings].

We report herein two cases of nemaline myopathy which showed peculiar muscle involvement and clinical symptoms. Case 1: A 44-year-old woman had developed gradual woresening of muscle weakness. Neurologically, only flexion of her neck was found to be weak. Her muscular CT revealed mild atrophy of four extremities and the sternocleidomastoid muscles. Histological examinations with Gomori-trichrome staining revealed tiny structures whose form was compatible with nemaline rods. Moreover, electronmicroscopic examination demonstrated the lattice pattern of electron-dense structures, and they also appeared to possess structural continuity with the Z-band. Case 2: A 56-year-old woman visited our department because of neck pulsations. Neurological examinations revealed bilateral hearing disturbance, marked atrophy of neck muscles, muscle weakness in four extremities and hypoactive deep tendon reflexes. She also exhibited steppage and waddling gaits. Her muscular CT demonstrated degenerative processes in the neck muscles(splenius muscles and semispinal muscles), trapezius muscles, para-spinal muscles, deltoid muscles and gluteal muscles. Among them, the para-spinal muscles and extensor muscles of the lower limbs showed marked degeneration and had been partly replaced by fatty tissues. A muscle biopsy was performed, and the presence of nemaline rods was confirmed by Gomori-trichrome staining. Although these two cases could be diagnosed as nemaline myopathy, the clinical symptoms and muscular CT findings were not quite the same. Whether these differences might simply indicate different clinical phases during the disease progression or be of further pathogenic significance still remains unclear. Additionally, since long-term follow-up studies of nemaline myopathy are quite rare, further follow-up examinations of these cases are necessary in order to understand the clinical and pathological alterations of nemaline myopathy.