Maria Jędrzejowska

Unaffected patients with a homozygous absence of the SMN1 gene

In this report, we present three families in which we identified asymptomatic carriers of a homozygous absence of the SMN1 gene. In the first family, the bialleleic deletion was found in three of four siblings: two affected brothers (SMA type 3a and 3b) and a 25-years-old asymptomatic sister. All of them have four SMN2 copies. In the second family, four of six siblings are affected (three suffer from SMA2 and one from SMA3a), each with three SMN2 copies. The clinically asymptomatic 47-year-old father has the biallelic deletion and four SMN2 copies. In the third family, the biallelic SMN1 absence was found in a girl affected with SMA1 and in her healthy 53-years-old father who had five SMN2 copies. Our findings as well as those of other authors show that an increased number of SMN2 copies in healthy carriers of the biallelic SMN1 deletion is an important SMA phenotype modifier, but probably not the only one.

Incidence of spinal muscular atrophy in Poland--more frequent than predicted?

Background: The application of molecular methods has enhanced and enlarged the diagnostics of spinal muscular atrophy (SMA) and its carriership. It allows for reliable epidemiological studies which are of importance to demography and genetic counseling. Methods: This study sought to evaluate the incidence of SMA in Poland, on the basis of the prevalence of the SMN1 gene deletion carrier state in the general population, as well as an analysis of all cases of SMA diagnosed in the years 1998–2005. Results: The prevalence of the SMN1 gene deletion carrier state was estimated at 1 per 35 persons (17/600), yielding an incidence of SMA equal to 1 per 4,900. By contrast, the incidence of SMA based on the results of the meta-analysis was an estimated 1 per 7,127 in Warsaw and 1 per 9,320 persons across Poland, suggesting that some cases of SMA remain undiagnosed. SMA1 predominated among the diagnoses, accounting for 69% of all cases. Conclusion: A high prevalence of the SMN1 deletion carrier state in the general population indicates that SMA could be a more frequent disease than is predicted by the epidemiological data regarding diagnosed cases.

Severe phenotypes of SMARD1 associated with novel mutations of the IGHMBP2 gene and nuclear degeneration of muscle and Schwann cells

Spinal muscular atrophy with respiratory distress type 1 (SMARD1) is a very rare autosomal recessive form of spinal muscular atrophy manifested in low birth weight, diaphragmatic palsy and distal muscular atrophy. Caused by a mutation in the IGHMBP2 gene, the disease is addressed here by reference to five Polish patients in which SMARD1 has been confirmed genetically. All presented a severe form of the disease and had evident symptoms during the second month of life; with four displaying weak cries, feeding difficulties and hypotonia from birth. Two were afflicted by severe dysfunction of the autonomic nervous system. Ultrastructural analysis of a muscle biopsy revealed progressive degeneration within the nuclei of the muscle cells and Schwann cells. Neuromuscular junctions were also defective. It proved possible to identify in our patients 6 novel IGHMBP2 mutations: three missense (c.595G>C, c.1682T>C and c.1794C>A), two nonsense (c.94C>T and c.1336C>T) and one in-frame deletion (c.1615_1623del). One nonsense mutation (c.429C>T) that had been described previously was also identified. Observation of our patients makes it clear that clinical picture is still the most important factor suggesting diagnosis of SMARD1, though further investigations concerning some of the symptoms are required. As the IGHMBP2 gene is characterized by significant heterogeneity, genetic counseling of affected families is rendered more complex. IGHMBP2 protein deficiency can lead to the degeneration of nuclei, in both muscle and Schwann cells.

Motor unit loss estimation by the multipoint incremental MUNE method in children with spinal muscular atrophy – A preliminary study

Quantitative EMG reflects denervation of muscles after lower motor neuron degeneration in spinal muscular atrophy (SMA) but does not reflect actual motor unit loss. The aim of our study was to assess the value of the multipoint incremental motor unit number estimation (MUNE) method in the modification by Shefner in estimating motor unit loss in SMA. The number of motor units, the mean amplitude of an average surface-detected single motor unit potential (SMUP), and the amplitude of compound motor action potentials (CMAP) were estimated in 14 children with SMA in the abductor pollicis brevis (ABP). Significant differences in MUNE values and SMUP and CMAP amplitude were found between the SMA and control groups (P < 0.0001). MUNE values correlated with Hammersmith Functional Motor Scale (HFMS) scores (P < 0.05). Increased SMUP amplitude values correlated with decreased HFMS scores (P < 0.05). The study confirms that MUNE method in the modification by Shefner is a useful tool reflecting motor unit loss in SMA, and it is easy to perform and well tolerated. MUNE and SMUP amplitude seemed to be sensitive parameters reflecting motor dysfunction in SMA but a longitudinal study in a larger number of subjects is needed.

Novel point mutations in survival motor neuron 1 gene expand the spectrum of phenotypes observed in spinal muscular atrophy patients

The aim of our study was to identify point mutations in a group of 606 patients diagnosed for spinal muscular atrophy with excluded biallelic loss of the SMN1 gene. Point missense mutations or small deletions in the SMN1 gene were ultimately identified in 18 patients. Six patients were found to have small deletions, the c.429_435del mutation in 3 cases, the c.431delC mutation in 2 and c.722delC in one. Those mutations, not described previously, were characteristic of patients presenting a severe phenotype. The most frequent missense mutation - p.Thr274Ile, was identified in 9 patients presenting a rather mild phenotype. Three other missense mutations, i.e., p.Ser230Leu, p.Ala111Gly and p.Pro244Leu, were identified in a further 3 SMA3 patients. Mutation p.Pro244Leu, not described so far, was identified in a patient with a mild form of SMA and more distal distribution of muscle weakness. Our results suggest a specific point mutation spectrum in the Polish population. The existence of small deletions not identified thus far could suggest a possible founder effect. In patients with preserved one SMN1 allele without common exon 7 deletion, presenting a mild form of SMA, a special consideration should be given to the p.Thr274Ile mutation.

SMN1 gene duplications are more frequent in patients with progressive muscular atrophy.

Abstract Survival Motor Neuron 1 (SMN1) is a causative gene for autosomal recessive infantile and juvenile proximal spinal muscular atrophy. SMN1 duplications have recently been found to increase susceptibility to amyotrophic lateral sclerosis. The role of centromeric SMN copy (SMN2) has been postulated in progressive muscular atrophy (PMA). The aim of this study was to analyse the SMN1 and SMN2 copy number variations in patients with PMA. SMN1 and SMN2 genotype was studied in 87 patients with PMA, diagnosed at the Department of Neurology, Medical University of Warsaw, between 1992 and 2012 and in 600 healthy controls. Results demonstrated that three copies of SMN1 were found in 8.1% of PMA patients and in 24% of PMA patients with disease duration above 48 months compared to 4.6% of the general population. Patients with three SMN1 copies had a limb onset, lower median age of onset and longer disease duration compared to patients with two SMN1 copies. There were no significant differences in the SMN2 copy numbers. In conclusion, the increased copy number of SMN1 may be a susceptibility factor to PMA and influence the clinical phenotype.

A patient with both Charcot-Marie-Tooth disease (CMT 1A) and mild spinal muscular atrophy (SMA 3).

In the present study, we report a single Polish SMA family in which the 17p11.2-p12 duplication causative for the Charcot-Marie-Tooth type 1A disease (CMT1A) was found in addition to a deletion of exons 7 and 8 of the SMN1 gene. A patient harboring both SMA and CMT1A mutations manifested with SMA3 phenotype and foot deformity. Her electrophysiological testing showed chronic neurogenic changes in proximal muscles that are typical for SMA, but also slowed conduction velocity in motor and sensory fibers that is typical for demyelinating neuropathy.

X-linked spinal muscular atrophy (SMAX2) caused by de novo c.1731C>T substitution in the UBA1 gene

Infantile X-linked spinal muscular atrophy (SMAX2) is a rare form of spinal muscular atrophy manifesting as severe hypotonia, areflexia, arthrogryposis, facial weakness and cryptorchidism, and frequently accompanied by bone fractures. We present a male patient with SMAX2 who presented with typical symptoms at birth, preceded by reduced fetal movements in the second and third trimesters of pregnancy. Clinical examination revealed a myopathic face with a characteristic tent-shaped open mouth, tongue fibrillations, profound muscle weakness, areflexia, multiple contractures, mild skeletal abnormalities and cryptorchidism. In the first days of the patients life, fractures of the right femur and right humerus were found; however, calcium-phosphate metabolism and densitometric examination were normal. Molecular analysis revealed a de novo c.1731C>T substitution in the UBA1 gene, which was localized in exon 15, the specific hot spot for mutation.

A novel COL12A1 variant expands the clinical picture of congenital myopathies with extracellular matrix defects

Mutations in the COL12A1 (collagen, type XII, alpha 1) gene have been described in a milder Bethlem‐like myopathy in 6 patients from 3 families (dominant missense), and in a severe congenital form with failure to attain ambulation in 2 patients in a single pedigree (recessive loss‐of‐function).

The remarkable phenotypic variability of the p.Arg269HiS variant in the TRPV4 gene: p.Arg269HiS mutation in TRPV4

Introduction: Mutations in the TRPV4 gene are associated with neuromuscular disorders and skeletal dysplasias, which present a phenotypic overlap. Methods: Next‐generation sequencing and Sanger sequencing were used to analyze the TRPV4 gene. Results: We present 2 Polish families with TRPV4‐related disorder harboring the same p.Arg269His mutation. The disease phenotypic expression was extremely variable (from mild scapular winging to severe hypotonia, global weakness, inability to walk unaided, congenital contractures, scoliosis, and respiratory insufficiency), but did not suggest anticipation. The 2 most severely affected patients showed congenital distal contractures of the upper limbs and involvement of cranial nerves (manifesting as facial asymmetry and strabismus). The disease course seemed to be stable, although in later stages it caused respiratory insufficiency and progression of physical disability. Discussion: The phenotypic variability observed in p.Arg269His carriers suggests that an additional modifier or a more complex pathogenic mechanism exists. Muscle Nerve 59:129–133, 2019