Distal Muscles Research Articles

Deep Brain Stimulation for Holmes Tremors and Literature Review.

Deep Brain Stimulation for Holmes Tremors and Literature Review.

Challenges in evaluating forearm muscle activity based on the compound muscle action potential of the flexors of the whole forearm

ObjectiveMuscle strength, which correlates with the compound muscle action potential (CMAP), can also be estimated by measuring the CMAP. Therefore, we evaluated the CMAP of the flexor muscles of the whole forearm to identify their muscle strength. MethodsFourteen healthy volunteers were enrolled. The elbow was determined to be the stimulation point, and the recording site for the flexor muscles of the whole forearm was set at approximately 8 cm distal to the elbow. We prospectively evaluated the baseline-to-peak amplitude of the CMAP of the whole forearm flexor muscles (WFFM), including that obtained from the median nerve stimulation (WFFMm), ulnar nerve stimulation (WFFMu), and their sum (WFFMsum). Additionally, we analyzed the relationships between WFFMm and WFFMu amplitudes with other quantitative parameters, including grip strength and routine CMAP amplitudes. ResultsThe CMAP’s test–retest analysis revealed high reliability. Grip power was significantly correlated with WFFMm and WFFMsum and mildly correlated with WFFMu. Tip-pinch strength with WFFMm and flexor pollicis longus (FPL) measurements correlated significantly. Lateral-pinch strength was significantly correlated with the first dorsal interosseous muscle (FDI) measurements but not with WFFM. The abductor digiti minimi (ADM) and abductor pollicis brevis (APB) were not correlated with grip power or pinch strength. ConclusionsBy electrophysiology examination, this study demonstrated that WFFMm is involved in grip power and other pinch strengths. This method may serve as a novel tool for measurement of distal muscle strengths. SignificanceThis is the first study to attempt to evaluate the muscle strength of forearm flexor muscles by measuring the CMAP.

A rare case of type1 proximal spinal muscular atrophy (werdnig - hoffmann disease) – a case report and review of literature

Spinal Muscular Atrophy (SMA) is an autosomal recessive Motor Neuron Disease (MND) with mutation of Survival motor neuron 1 (SMN1) gene located in chromosome 5(5q13.2) characterized by diffuse proximal and distal muscle weakness. Here the authors report a case of SMA in a 3 months old male infant with hypotonia of proximal muscles in both upper limbs and lower limbs with characteristic fasciculations of tongue and confirmed by genetic studies.

LOCOMOTOR KINETICS OF THE LOWER EXTREMITIES IN HEALTHY INDIVIDUALS AND IDIOPATHIC SCOLIOSIS

Aim: The definition of «muscle contractile reserve» is a prognostic criterion in assessing locomotor capabilities. Material and methods: Groups of adolescents: 1-healthy, 2-idiopathic scoliosis. Research methods: dynamometry, 3D video analysis of gait. Results: In AIS, the relative isometric moment of force is reduced compared to healthy ones: in hip extensors by 36% (p=0.00106), hip flexors by 33% (p=0.0002), hip abductors by 38% (p=0003), leg extensors by 37% (p=3.22E-07), leg flexors by 42% (p=4.15E-06). In healthy adolescents, the muscle reserve at a walking speed of 3.7-4.3 km/h was: in hip extensors and flexors 65-75%, hip adductors 30-40%, hip abductors — 80-90%, leg extensors — 70-80%, leg flexors — 80-90% and dorsal foot flexors — 75-90%. The kinetic values of the plantar flexors exceed the isometric maximum when the foot is placed at an angle of 90° by 30-40%. In AIS the distal muscle groups had no signs of functional damage; proximal muscle groups showed asymmetry (up to 25%) and a decrease in strength in the isometric mode by 33-42%. Muscle reserve at the same speed is reduced for anti-gravity muscles in AIS: in hip extensors by 40% and in leg extensors by 70%. The total joints power did not significantly differ from the control group. Conclusions: In locomotor stereotypes in patients with scoliosis, there was a pattern of adaptive redistribution of the kinetic potential of the contractile function from one joint muscle to another.

Relationship between Clinical Severity and Cross-sectional Area of Ultrasonographic Examinations in Ulnar Neuropathy at the Elbow.

This study explored the relationship between clinical severity of ulnar neuropathy at the elbow (UNE) and ulnar nerve cross-sectional area (CSA) by ultrasound examination to identify appropriate measurement sites for UNE diagnosis and evaluation. In this retrospective analysis, we examined the arms of 37 patients diagnosed with UNE and those of 34 individuals as controls. The ulnar nerve CSAs were measured at 2 cm distal to the tip of the medial epicondyle (dME), the tip of the medial epicondyle (ME), 2 cm proximal to the tip of the medial epicondyle (pME), and any site showing the maximum CSA between the dME and pME (largest dpME). The modified McGowan classification (grades I, IIA, IIB, and III) was used to rate the clinical severity of UNE. For all sites, the CSAs were significantly correlated with clinical severity. The sites showing the maximum CSA were inconsistent between controls and grade IIA patients. Grade IIB patients showed the largest CSA at the ME in the majority of patients. In grade III patients, maximum CSA occurred only at the ME. Serial assessment to detect nerve enlargement at multiple sites was beneficial for mild UNE patients with weakness of the ulnar distal muscles with Medical Research Council (MRC) score of 4 or higher (grade IIA). For severe UNE patients with weakness of the ulnar distal muscles classified as MRC3 or less (grades IIB, III), the most efficient method for detecting enlarged nerves was to initially measure the CSA at the ME.

Chapter 2 - Upper and lower motor neuron neurophysiology and motor control

This chapter considers the principles that underlie neurophysiological studies of upper motor neuron or lower motor neuron lesions, based on an understanding of the normal structure and function of the motor system. Human motor neurophysiology consists of an evaluation of the active components of the motor system that are relevant to volitional movements. Relatively primitive motor skills include locomotion, much dependent on the spinal cord central pattern generator, reaching, involving proximal and distal muscles activation, and grasping. Humans are well prepared to perform complex movements like writing. The role of motor cortex is critical for the motor activity, very dependent on the continuous sensory feedback, and this is essential for adapting the force and speed control, which contributes to motor learning. Most corticospinal neurons in the brain project to brainstem and spinal cord, many with polysynaptic inhibitory rather than excitatory connections. The monosynaptic connections observed in humans and primates constitute a specialized pathway implicated in fractional finger movements. Spinal cord has a complex physiology, and local reflexes and sensory feedback are essential to control adapted muscular contraction during movement. The cerebellum has a major role in motor coordination, but also consistent roles in sensory activities, speech, and language, in motor and spatial memory, and in psychological activity. The motor unit is the final effector of the motor drive. The complex interplay between the lower motor neuron, its axon, motor end-plates, and muscle fibers allows a relevant plasticity in the movement output.

What Garcia Got Right: Understanding Cortical Signaling of the Glottis

Phonation is a wonder of physics and physiology. In reductionist terms, the mechanics of the glottis can be viewed as a valve system: the streaming airflow from the lungs is passed through a dynamic and complex structure which is constantly changing aperture and configuration. The resulting pressure waves from air passing through the glottis are ultimately shaped and refined by the vocal tract giving rise to our unique voices. The nuance of this is extraordinary: as we sing and speak the vocal fold configuration is constantly changing in length and degree of contact under pressure conditions which are not always predictable. Yet the folds remain remarkably diligent in their ability to maintain equilibrium throughout these rapid changes. Without such discipline of this mechanism, we wouldn’t be capable of getting stability in any sound. Large, distal muscles of respiration are not designed to regulate such nuance at the millisecond level. So it is left to the larynx and vocal folds to balance the source sound of the system.This installment of “Minding the Gap” will be about how the brain controls this valve element at the center of our instrument: the intricate behaviors of the glottis. Neuroscience has shown that voicing, pitch, and phrasing are all signaled independently through the two laryngeal motor cortices which are a hallmark of our vocal learning abilities. Understanding these elements can help singers and teachers design targeted pedagogical strategies.

Compound muscle action potential duration ratio for differentiation between Charcot-Marie-Tooth disease and CIDP

ObjectiveTo elucidate the utility of the proximal to distal compound muscle action potential (CMAP) duration ratio to distinguish between demyelinating Charcot-Marie-Tooth disease (CMT) and chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) compared with nerve ultrasound. MethodsThirty-nine demyelinating CMT patients and 19 CIDP patients underwent nerve conduction studies (NCS) and nerve ultrasound. NCS parameters including CMAP duration ratio calculated by dividing the value at the proximal site by that at the distal site and nerve cross-sectional area (CSA) measured by ultrasound were compared between the two groups. The diagnostic sensitivity and specificity of each parameter were analysed. ResultsCMT patients showed a significantly lower CMAP duration ratio than CIDP patients (p < 0.05). The area under the curve (AUC) value of the CMAP duration ratio exceeded 0.95 when CMT was considered “positive”, and a cut-off value of 1.13 resulted in high diagnostic sensitivity and specificity (84.6 and 100 % for median nerve, 97.4 and 85.7 % for ulnar nerve, respectively), whereas the AUC value of nerve CSA ranged from 0.70 to 0.81. ConclusionsThe CMAP duration ratio could effectively distinguish between demyelinating CMT and CIDP. SignificanceAdding the CMAP duration ratio to a routine NCS may improve the accuracy of the diagnosis of demyelinating CMT.

357: MORE THAN MYALGIA: STATIN-INDUCED IMMUNE-MEDIATED NECROTIZING MYOPATHY

Introduction: Statins rank amongst the top ten most prescribed medications in the United States for their cardiovascular benefits. Common toxic side effects include elevated liver enzymes and myalgia including rhabdomyolysis. We report a case of a previously healthy middle-aged female who recently started statin therapy and developed progressive muscle weakness requiring mechanical ventilation. Description: A 58-year-old female with recently diagnosed hyperlipidemia started on atorvastatin (40 mg) 2 months prior to presentation was admitted with 2 weeks of progressively worsening proximal muscle weakness and oropharyngeal dysphagia. Admission labs showed a significantly elevated creatine phosphokinase (CPK) (3,742 U/L) and aldolase level (41.1 U/L). She was empirically started on IVIG for presumed myasthenic crisis or possible inflammatory myositis. On day 2, she exhibited worsening proximal muscle weakness and an inability to lift her extremities against gravity. On physical exam, she had 1/5 strength of proximal muscle groups and 4/5 strength of distal muscle groups with an otherwise intact neuromuscular exam. On day 3, she had worsening dysphagia and aspiration pneumonitis requiring endotracheal intubation. An EMG showed myopathic features in the proximal musculature without any evidence of neuropathy. She was empirically started on steroids with some improvement. After 1 week, the anti-HmgCoA reductase antibody returned severely positive (>200). Given the high specificity of this test, her presentation was ultimately deemed consistent with statin induced immune-mediated necrotizing myopathy, and she was started on Cellcept (MMF) and high-dose steroids. Discussion: The case highlights the devastating consequences that can result from a very commonly prescribed medication class and the importance of actively evaluating for adverse medication effects. Statin therapies are guideline directed in patients with cardiovascular disease such as coronary artery disease and stroke. Myalgia without significant weakness are a common side effect and therapy includes discontinuing the offending agent. In the presence of severe weakness, statin induced immune-mediated necrotizing myopathy should be considered, as it could be detrimental and may require mechanical ventilation and treatment with immunosuppressants.

Conduction block and positive sharp waves/fibrillation potentials in entrapment neuropathies of the ulnar, radial, and peroneal nerves

Introduction: Entrapment mononeuropathies can cause motor conduction block, positive sharp waves, and fibrillation potentials. Aim: The study aims to find whether there is a relationship between positive sharp waves/fibrillation potentials and conduction block observed in entrapment mononeuropathies. Materials and methods: Patients with ulnar neuropathy at the elbow, radial neuropathy at the spiral groove, and peroneal neuropathy at the fibular head were included in this retrospective study. Nerve conduction study and needle electromyography results of the patients were analysed. Results: The study included a total of patients with 67 ulnar neuropathy, 8 radial neuropathy, and 27 peroneal neuropathy. All radial and peroneal neuropathy patients and 30 ulnar neuropathy patients had positive sharp waves/fibrillation potentials in at least one muscle. Twenty-three ulnar neuropathy patients with these potentials, 6 radial neuropathy patients, and 18 peroneal neuropathy patients had conduction block (p &lt; 0.001). The reduction of compound muscle action potential amplitude in percentage recorded from the abductor digiti quinti/first dorsal interosseous across the elbow segment in ulnar neuropathy patients with and without positive sharp waves/fibrillation potentials was 41.9 ± 35.9/46.6 ± 36.1% and 7.6 ± 16.5/10.4 ± 16.5%, respectively (p &lt; 0.001/p &lt; 0.001). The distal compound muscle action potential amplitudes of ulnar neuropathy patients with these potentials were lower than those of ulnar neuropathy patients without these potentials (p = 0.029 – abductor digiti quinti, p = 0.017 – first dorsal interosseous). No correlation was found between the severity of positive sharp waves/fibrillation potentials and muscle strength in patients with these potentials (p &gt; 0.05). Conclusions: Positive sharp waves/fibrillation potentials and motor conduction block can be seen together in patients with entrapment mononeuropathies. We concluded that there may be no relationship between the severity of these potentials and muscle strength.

Wasted leg syndrome: An atypical slowly-progressive form of lower motor neuron disease

We describe four male patients with wasted-leg syndrome, with predominant asymmetric thigh atrophy and weakness that stabilized after a period of slow progression (follow-up 7–18 years). Two patients had an Indian ethnic background and two were Portuguese, without known Indian ancestry. Other mimicking disorders were excluded, but one Indian patient was later diagnosed with CADASIL. Electromyography (EMG) revealed severe chronic neurogenic changes in proximal leg muscles, and mild changes in distal leg muscles, but EMG of the upper limbs was normal. Upper motor neuron signs were absent clinically and on transcranial magnetic stimulation. This seems to represent a variant of the common wasted-leg syndrome presentation.

Deep-time invention and hydrodynamic convergences through amniote flipper evolution.

The diapsid plesiosaurs were pelagic and inhabited the oceans from the Triassic to the Cretaceous. A key evolutionary character of plesiosaurs is the four wing-like flippers. While it is mostly accepted that plesiosaurs were underwater fliers like marine turtles, penguins, and maybe whales, other swimming styles have been suggested in the past. These are rowing and a combination of rowing and underwater flight (e.g., pig-nosed turtle, sea lion). Underwater fliers use lift in contrast to rowers that employ drag. For efficiently profiting of lift during underwater flying, it is necessary that plesiosaurs twisted their flippers by muscular activity. To research the evolution of flipper twisting in plesiosaurs and functionally analogous taxa, including turtles, we used anatomical network analysis (AnNA) and reassessed distal flipper muscle functions. We coded bone-to-bone and additionally muscle-to-bone contacts in N × N matrices for foreflippers of the plesiosaur, the loggerhead sea turtle, the pig-nosed turtle, the African penguin, the California sea lion, and the humpback whale based on literature data. In "R," "igraph" was run by using a walktrap algorithm to obtain morphofunctional modules. AnNA revealed that muscle-to-bone contacts are needed to detect contributions of modules to flipper motions, whereas only-bone matrices are not informative for that. Furthermore, the plesiosaur, the marine turtles, the seal, and the penguin flipper twisting mechanisms, but the penguin cannot actively twist the flipper trailing edge. Finally, the foreflipper of the pig-nosed turtle and of the whale is not actively twisted during swimming.

Systematic determination of muscle groups and optimal stimulation intensity for simultaneous TMS mapping of multiple muscles in the upper limb.

Transcranial magnetic stimulation has been used to assess plastic changes in the cortical motor representations of targeted muscles. The present study explored the optimal settings and stimulation intensity for simultaneous motor mapping of multiple upper-limb muscles across segments. In 15 healthy volunteers, we evaluated cortical representations simultaneously from one muscle in the shoulder, two in the upper arm, two in the forearm, and two intrinsic hand muscles, using five stimulation intensities, ranging from 40% to 100% of the maximum stimulator output. We represented the motor map area acquired at each intensity as a percentage of the maximum for each muscle. We defined a motor map area between 25% and 75% of the maximum as the optimal area size with sufficient scope for both up- and down-regulation, and stimulation intensities producing the map area size within this range as the optimal intensities. We found that motor maps with optimal area sizes could be produced simultaneously for the four distal muscles of the forearm and hand in most participants when the stimulation intensity was set at 120-140% of the resting motor threshold (RMT) of the first dorsal interosseous. For the remaining three proximal muscles, motor maps with optimal area sizes were produced only in a few participants, even when using a higher intensity (180-220% RMT). These findings suggest that cortical representations can be assessed simultaneously in a group of distal muscles using a relatively low stimulation intensity, while a separate operation is required to assess that of the proximal muscles.

Finger Flexor Weakness in Myasthenia Gravis.

Myasthenia gravis (MG) affects the ocular, bulbar, and proximal limb muscles. The involvement of distal limb musclesis uncommon. MG-related weakness that severely affects the finger flexors and spares finger extensors and intrinsic hand muscles have never been reported. Here, we report a 35-year-old woman with acetylcholine receptor-antibody positive generalised MG who presented with severe bilateral asymmetric (left worse than right) finger flexor weakness during an MG relapse. The remaining muscles including the median and ulnar intrinsic hand muscles were normal. Repetitive nerve stimulation test showed decremental responses of more than 10%. Magnetic resonance imaging showed short-T1 inversion recovery sequences and increased signal intensities in the volar forearm muscles. Needle electromyography revealed fibrillations and positive sharp waves, small amplitude, short-duration, and polyphasic early recruiting motor unit action potentials. Myositis-specific autoantibodies were negative. Muscle biopsy showed neurogenic features. The patient had a good recovery with immunotherapy. We conclude that clinicians should be aware that marked weakness of the finger flexors can occur as a result of an MG relapse and may require early aggressive therapy. Key Words: Electromyography, Finger flexors, Muscle, Biopsy, Myasthenia gravis.

Novel mutation in the MPZ gene causes early-onset but slow-progressive Charcot–Marie–Tooth disease in a Russian family: a case report

Charcot-Marie-Tooth disease (CMT) is a genetically heterogeneous group of peripheral neuropathies most of which are associated with mutations in four genes including peripheral myelin protein-22 (PMP22), myelin protein zero (MPZ), gap junction protein beta1 (GJB1) and mitofusin2 (MFN2). This current case report describes the clinical and genetic characteristics of a 6-year-old male proband. A physical examination revealed muscular hypotonia. He started walking on his own at 18 months. A nerve conduction study with needle electromyography revealed conduction block. A novel MPZ mutation (c.398C > T, p.Pro133Leu) was revealed in the proband. This mutation was also found in the 32-year-old father of the proband. The father had had deformity of the feet and distal muscle weakness since childhood. The novel p.Pro133Leu pathogenic mutation was responsible for early onset but slowly progressive CMT1B. We assume that this site is an intolerant to change region in the MPZ gene. This variant in the MPZ gene is an important contributor to hereditary neuropathy with reduced nerve conduction velocity in the Russian population. This case highlights the importance of whole exome sequencing for a proper clinical diagnosis of CMT associated with a mutation in the MPZ gene.

Whole-muscle fat analysis identifies distal muscle end as disease initiation site in facioscapulohumeral muscular dystrophy

BackgroundFacioscapulohumeral dystrophy (FSHD) is a major muscular dystrophy characterized by asymmetric fatty replacement of muscles. We aimed to determine the initiation site and progression profile of the disease in lower extremity muscles of FSHD patients by assessing fat infiltration along their full proximo-distal axis using quantitative MRI.MethodsNine patients underwent MRI of lower extremities to assess end-to-end muscle fat fractions (FFs) and inflammatory lesions. Seven patients underwent the same MRI ~3.5 years later. Individual muscles (n = 396) were semi-automatically segmented to calculate average FFs over all slices covering whole muscles. To assess disease progression we determined FF changes in 5 adjacent muscle segments.ResultsWe provide evidence that fat replacement commonly starts at the distal end of affected muscles where the highest FFs occur (p < 0.001). It progresses in a wave-like manner in the proximal direction at an increasing rate with the highest value (4.9 ± 2.7%/year) for muscles with baseline FFs of 30–40%. Thereafter it proceeds at a slower pace towards the proximal muscle end. In early phases of disease, inflammatory lesions preferentially occur at the distal muscle end. Compared with whole-muscle analysis, the common FF assessments using only few MR slices centrally placed in muscles are significantly biased (~50% in progression rate).ConclusionsThese findings identify the distal end of leg muscles as a prime location for disease initiation in FSHD and demonstrate a wave-like progression towards the proximal end, consistent with proposed disease mechanisms. End-to-end whole-muscle fat assessment is essential to properly diagnose FSHD and its progression.

Dual Venous Drainage for the Free Latissimus Dorsi Muscle Flap-Using the Serratus Vein Tributary-Making Virtue of a Necessity.

Background Most flap failures in the lower limb are on account of venous congestion. Literature shows a decrease in the incidence of venous failure when two veins are anastomosed. The thoracodorsal pedicle of the latissimus dorsi free flap affords the possibility of a single venous anastomosis. The lack of a second venous outflow could result in venous congestion in the distal limits of the flap, particularly when long flaps are required for large defects or when the recipient veins are smaller in diameter. Methods We describe a consecutive series of 11 cases of latissimus dorsi flaps for leg and foot defects with a mean defect size of 310 cm 2 , where the serratus anterior vein was used as a second venous outflow channel to ensure maximal venous drainage. Results There were no re-explorations for anastomotic causes. Only one case had partial distal muscle necrosis. There was a delayed anastomotic blowout due to infection resulting in amputation in one case. There was no partial distal muscle necrosis in nine of the ten cases. Conclusion Using the serratus vein as a second venous outflow is of use in reducing incidence of venous occlusion and distal muscle necrosis and can be specially indicated for large flaps and venous diameter discrepancy.

CASQ1‐related myopathy: The first report from China and the literature review

Calsequestrin 1 (CASQ1) is the most crucial Ca2+ binding protein localized in the sarcoplasmic reticulum (SR) of skeletal muscle. With high capacity and low affinity for Ca2+, CASQ1 plays a significant role in maintaining a large amount of Ca2+ necessary for muscle contraction. However, only five mutations in CASQ1 have been identified to date. Here, we report a 42-year-old Chinese female patient who presented with a 12 years history of slowly progressive upper limb weakness, predominantly affecting distal muscles, which was uncommon comparing to other CASQ1-related patients. Next-generation sequencing (NGS) analysis revealed a novel heterozygous mutation (c.766G > A, p.Val256Met) in CASQ1. Functional studies confirmed the likely pathogenicity of this variant. Muscle histopathology revealed rare optically empty vacuoles in myofibers and atypical eosinophilic granules in the cytoplasm, which has not been observed before. We also performed a literature review on all the pathogenic mutations in CASQ1 and summarized their genetic and clinical characteristics. This is the first report on CASQ1-related myopathy from China, further expanding the mutation spectrum of CASQ1 gene and provides new insights into the function of CASQ1.

Do patients with Hirayama disease require surgical treatment? A review of the literature.

The main clinic characteristic of Hirayama disease (HD) is atrophy of the distal muscles in the upper limbs. Recently, an increasing number of HD cases have been reported. Many HD patients have persistently progressive symptoms and conservative treatments failed. This article aims to review the current status of the field and summarizes the main surgical treatment options for patients with HD. A comprehensive search of the PubMed and the Web of Science databases was conducted from their inception to September 15th, 2022. Search terms included "juvenile muscular atrophy of upper extremity", "Hirayama disease" and "surgery". A total of 169 relevant publications were identified and 29 articles were finally reviewed. Current surgical treatments for HD are either anterior cervical surgery or posterior cervical surgery. The two approaches can effectively stop the disease. However, no studies have compared the advantages and limitations of the two surgical methods. The previous view that HD can be improved with conservative treatment has been challenged. In many studies, surgical treatment has been shown to improve the hand function in patients with HD. However, there is still controversy about the methods of anterior and posterior cervical surgery. Future research could focus on exploring the advantages and limitations of different surgeries.

Pathogenic variants in three families with distal muscle involvement

Three families suspected of distal hereditary motor neuropathy underwent genetic screening with the aim to identify the molecular defect underlying the disease. The description of the identification reflects the shift in molecular diagnostics that was made during the last decades. Our candidate gene approach yielded a known pathogenic variant in BSCL2 (p.Asn88Ser) in one family, and via a CMT-capture, in HSPB1 (p.Arg127Trp), in addition to five other variations in Charcot-Marie-Tooth-related genes in the proband of the second family. In the third family, using whole exome sequencing, followed by linkage-by-location, a three base pair deletion in exon 33 of MYH7 (p.Glu1508del) was found, a reported pathogenic allele albeit for a myopathy. After identification of the causative molecular defect, cardiac examination was performed for patients of the third family and this demonstrated abnormalities in three out of five affected family members. Heterogeneity and expansion of clinical phenotypes beyond known characteristics requires a wider set of genes to be screened. Whole exome/genome analysis with limited prior clinical information may therefore be used to precede a detailed clinical evaluation in cases of large families, preventing screening of a too narrow set of genes, and enabling the identification of novel disease-associated genes. In our cases, the variants had been reported, and co-segregation analysis confirmed the molecular diagnosis.