Neck Muscle Weakness Research Articles

PP09.7 – 2375: Phenotypic heterogeneity in two large Roma families with a congenital myasthenic syndrome due to CHRNE1267delG mutation. A long-term follow-up

Objective Mutations in CHRNE are the cause of approximately 50% of CMS. ɛ1267delG frameshifting mutation is present on at least one allele of 60% of patients with CHRNE mutations. We here present a description of the clinical features of the CMS caused by the homozygous 1267delG mutation in the AChR ɛ subunit in 13 members of two large Roma kindreds. Methods Thirteen patients from two unrelated families were followed up over a mean period of 9.9 years. Results We trace 65 and 108 members in six and seven generations of each family, respectively. We interviewed and examined 13 clinically affected family members, 9 women and 4 men. Disease onset ranged from first weeks after birth to 12 years (mean 3.7 years; median 2 years). Ophthalmoparesis was observed in nine patients and subjective diplopia was present in all thirteen cases. Bilateral symmetric ptosis was found in ten patients. Facial weakness was encountered in eleven patients. Mild bulbar symptoms were reported in ten patients. Proximal muscle weakness was found in ten patients. It entailed restricted ambulation in 8 patients. A rapid progression of the disease was noted in two patients. The disease course have remained stable in eight patients. Three patients had a significant fluctuation of their symptoms. All the thirteen patients responded positively to pyridostigmine. In 6 patients, addition of 3,4-diaminopyridine resulted in further clinical improvement. Conclusion Founder European Roma mutation 1267delG leads to an heterogeneous phenotype with a varying severity. It is further characterized by ophthalmoplegia and a good response to anticholinesterase drugs and 3,4-DAP; but also by ptosis, facial weakness, bulbar symptoms, neck muscle weakness, and proximal muscle weakness that entails the loss of ambulation in 63% of our adult patients. The disease course can be stable but also progressive in nearly 40%, with or without fluctuations.

Clinico pathological study of adult dermatomyositis: Importance of muscle histology in the diagnosis.

Aims:To study the histological features on muscle biopsy and correlate them with clinical features, other laboratory data in adult patients to make a diagnosis of dermatomyositis (DM), applying the European Neuromuscular center (ENMC) criteria.Materials and Methods:Adult patients who fulfilled clinical, laboratory, and muscle biopsy findings according to ENMC criteria for DM during the period 2010–2013 were included in the study. Cryostat sections of muscle biopsy were reviewed with emphasis on Perifascicular atrophy (PFA), perivascular/endomysial inflammation. Muscular dystrophies and metabolic myopathies were excluded by appropriate immunohistochemistry and special stains.Results:The diagnosis of adult DM was made in 45 patients out of 170 clinically suspected idiopathic inflammatory myopathies. These included 33 definite, 4 probable, 7 possible sine dermatitis, and 1 amyopathic DM. All patients with definite DM had typical rash and proximal muscle weakness and muscle biopsy showed PFA with or without inflammation. Thirteen patients had quadriparesis, neck muscle weakness, dysphagia/dysphonia at presentation. Patients with probable DM had rash and showed perivascular/endomysial inflammation with no PFA. Possible DM sine dermatitis showed PFA with perivascular/endomysial infiltrates. One patient of amyopathic DM had typical heliotrope rash and characteristic skin biopsy.Conclusions:Histological features are important for the diagnosis of DM. Relying on PFA for diagnosis of definite DM underestimates the true frequency of DM.

P1030: Clinical and electrophysiological follow-up study of a patient with congenital myasthenic syndrome (CMS) associated with mutations in the gene of the agrin (AGRN)

Objective We describe the clinical and electrophysiological findings of a severe form of congenital myasthenic syndrome (CMS) caused by two heteroallelic mutations in the gene encoding agrin (AGRN). Patient and methods A 43 year-old-man, born after a normal pregnancy at term, presented with generalized hypotonia in the first months of life. He walked at 12 months but soon developed ptosis, neck and truncal muscle weakness progressed slowly. There was arreflexia with flexor plantar responses. He never had sensory symptoms. Parents were normal; an older brother with a similar condition died at15. Electrophysiological investigations were performed on many occasions; blood count and chemistries of serum and CSF were normal. Antibodies against AChR, MuSK, and P/Q voltage-gated were negative. Results NCS were normal. RNS (3 Hz) of the median nerve induced a 40% decrement in the Thenar CMAP that improved markedly after exercise and Neostigmine. SFEMG showed increased jitter and blocking. Ultrastructure of muscle showed small nerve terminals, simplified postsynaptic folds, and disruption of their architecture. Genetic analysis revealed a nonsense and a missense mutations in the gene encoding agrin (AGRN). Conclusion These findings demonstrate that the AGRN mutations can cause a disruption of the architecture of the neuromuscular junction that results in a severe CMS.

Heterozygous D90A-SOD1 mutation in a patient with facial onset sensory motor neuronopathy (FOSMN) syndrome: a bridge to amyotrophic lateral sclerosis

ObjectiveTo describe a patient with facial onset sensory motor neuronopathy (FOSMN) syndrome associated with a heterozygous D90A mutation in superoxide dismutase (SOD1) gene.MethodsThe patient underwent neurological and neurophysiologic examinations, including...

Congenital Muscular Torticollis and Positional Plagiocephaly

Congenital Muscular Torticollis and Positional Plagiocephaly

Congenital Muscular Torticollis and Positional Plagiocephaly

On the basis of observational studies, child health practitioners in primary care settings should consider the diagnosis of congenital muscular torticollis (CMT)in infants with risk factors from birth history for intrauterine malpositioning or constraint (C). On the basis of observational studies, CMT is often associated with other conditions, including positional plagiocephaly and gross motor delays from weakened truncal muscles and/or lack of head control in early infancy (C). On the basis of observational studies, child health practitioners should counsel parents that infants should be on their stomachs frequently whenever they are awake and under direct adult supervision to develop their prone motor skills (C). On the basis of consensus, early identification of CMT(with or without positional plagiocephaly) and prompt referral to a physical therapist experienced in the treatment of CMT should be considered to avoid more costly or invasive treatments, such as cranial orthoses or surgery (D).

Elastic head support for persons with amyotrophic lateral sclerosis.

This article describes an inexpensive elastic head support for persons with amyotrophic lateral sclerosis (ALS) and neck muscle weakness and also presents a case series to examine its effectiveness. The device offers support to the head while the user is seated, standing, and walking, providing support for persons in various stages of ALS. The head support system was tested in seven male patients with ALS. Before and after the 2 wk trial, the subjects answered questions related to their communication efficacy, difficulty swallowing, level of neck discomfort, number of hours being upright before neck discomfort, comfort in social settings, and rating of perceived dyspnea. Subjects also answered specific questions related to the elastic head support after the 2 wk trial. The results suggested that the elastic head support is useful for some, but not all, patients.

Rabies Meningoencephalomyelitis presenting as Guillain Barré Syndrome

A 20-year-old male, hailing from Haryana, presented to medicine emergency in the month of October, with 5 days history of acute onset paralysis of all four limbs, worsening to involve the respiratory and truncal muscles. Illness was preceded by fever lasting for 3 days. He had history of dog bite with inadequate postexposure vaccination, 3 months prior to the current illness. On examination, there was hypotonia, arreflexic quadriparesis along with respiratory, bifacial, palatal, neck and truncal muscle weakness. He developed photophobia, neck stiffness, worsening sensorium and respiratory efforts, for which he was managed with mechanical ventilation in intensive care unit (ICU) setting. Investigations revealed mild leukocytosis (TLC: 12,800) and normal electrolytes, renal function test, chest X-ray and ECG. CSF revealed neutrophilic pleocytosis (100 cells P70 L30) and elevated protein with normal sugars (Pr/S: 120/60; corresponding blood sugar (CBS): 97 mg/dl). Human immunodeficiency virus (HIV) serology was negative, X-ray chest was within normal limits. Nerve conduction study was suggestive of sensorimotor axonal polyradiculopathy [Rt median CMAP reduced, Rt ulnar, peroneal, tibial were nonstimulable, Rt median and ulnar sensory nerve action potential (SNAP) was reduced]. Corneal smear was negative for rabies antigen and contrastenhanced magnetic resonance imaging (CE-MRI) brain was planned. A clinical possibility of Landry Guillain-Barre syndrome (LGBS) and rabies was kept. The patient could not afford intravenous immunoglobulins (IVIG) or plasmapheresis, and so he was started on injection methylprednisolone, 1 gm bolus once a day and empirically covered for bacterial meningitis with antibiotics. Other supportive measures continued. During the stay, he also had fluctuations in blood pressures with minimum of 110/70 to maximum of 150/90 mm Hg. On day third patient’s sensorium further worsened and cardiac monitor showed bradycardia, following which he sustained a cardiac arrest and could not be revived.

Incidence, predictors, and outcome of intermediate syndrome in cholinergic insecticide poisoning: A prospective observational cohort study

Context. Clinical manifestations and outcome of cholinergic insecticide poisoning is well studied. There are limited data on neuroparalytic features, predictors, and impact on mortality of intermediate syndrome. Methods. Patients admitted with history of insecticide exposure and cholinergic signs in a tertiary care center between April 2011 and March 2012 were followed up till recovery or death. While on standard care, development of intermediate syndrome was noted by neck and proximal muscle weakness, and/or signs of respiratory failure in the absence of cholinergic signs. Results. In 176 patients studied, incidence of intermediate syndrome was 17.6% (n = 31) with mean time of appearance of 44.5 ± 22.1 h after exposure (range 26 h– 5 days). Intermediate syndrome occurred in organophosphorus and carbamate poisoning (38.7% and 41.9%) and lasted for 1–7 days. All patients with intermediate syndrome developed weakness of neck and proximal muscles during the course; neck muscle weakness was the initial feature in majority of patients with respiratory failure (20/26). Age ≥ 45 (RR 2.23, 95% CI 1.14–4.38, p = 0.02), and dimethyl organophosphorus compounds (RR 4.87, 95% CI 1.82–13.04, p = 0.01) were found to be associated with development of intermediate syndrome while multiple gastric lavage was protective (RR 0.44, 95% CI 0.22–0.87, p = 0.001). Receiver operating characteristic curves were plotted for International Program on Chemical Safety Poison Severity Score (IPCS PSS) and Glasgow coma scale (GCS) on admission (AUC/sensitivity/specificity 0.77/0.94/0.6 for IPCS PSS > 2 and 0.64/0.71/0.65 for GCS ≤ 10). Overall mortality was 28.4% (n = 50); 40% (n = 20/50) occurred among intermediate syndrome patients with respiratory failure. Conclusion. As with exposure to organophosphorus, carbamate also result in intermediate syndrome; risk may be high with age ≥ 45, admission score of PSS > 2, and GCS ≤ 10. It can be detected early by identifying neck muscle weakness which aids in anticipating respiratory failure. Multiple gastric lavages may be protective; needs larger studies for clarification.

Abstract 27: A phase I study of MEK inhibitor BAY 86-9766 in Japanese patients with advanced or reflactory solid tumors.

Abstract Background: BAY 86-9766 (RDEA119) is a potent, orally administered,, allosteric inhibitor of mitogen-activated protein (MAP) kinase kinase (MEK) 1/2, a key protein in the MAP kinase signaling pathway, located downstream of RAS and RAF. We conducted a phase I study to evaluate the safety and pharmacokinetics (PK) of BAY 86-9766 in advanced/refractory Japanese cancer patients. Patients and Methods: BAY 86-9766 was administered at 30 mg bid (cohort 1) and at 50 mg bid (MTD; cohort 2) over a 28-day treatment cycle which was continued until disease progression or unacceptable toxicity. PK samples were collected after single doses (Day 1 to Day 4) and during multiple dosing through Day 22. Tumor response was assessed after every even cycle by RECIST v.1.1. Results: A total of 12 patients were enrolled, including 6 colorectal cancer, 2 GIST, and one hepatocellular cancer, carcinoid tumor, neuroendocrine tumor and leiomyosarcoma, respectively (5 patients in cohort 1: 30mg bid; 7 patients in cohort 2: 50mg bid). There were no DLTs in Cycle 1 of cohort 1 and cohort 2. The most common adverse event regardless of grade was rash acneiform in 12 subjects (100.0%), followed by elevated AST, creatine phosphokinase (CPK) or hypoalbuminemia in 9 subjects (75.0%), fever or elevated ALP in 7 subjects (58.3%), elevated ALT or decreased platelet count in 6 subjects (50.0%). Of those, the most common drug-related adverse events were rash acneiform (100.0%), followed by elevated CPK (66.7%), laboratory-others (66.7%), elevated AST (58.3%), and elevated ALP (50.0%). There were three cases of serious adverse events - thrombocytopenia, bile duct stenosis and elevated CPK - with only the elevated CPK being regarded as drug-related. There were no deaths on study. In Cohort 2, 7 out of 7 patients had elevated CPK, with 4 patients Grade 3 or higher. None of these were considered clinically significant and were not regarded as DLT's. Three patients had a positive de-challenge and re-challenge and 2 patients experienced muscle-related symptoms (neck pain and muscle weakness of the lower limb). PK parameters were comparable to the non-Japanese population. Conclusions: BAY 86-9766 was generally well tolerated at both the 30 mg bid dose and the MTD of 50 mg bid. BAY 86-9766 administration increased CPK in a majority of patients but this was manageable by dose reduction. Citation Format: Toshihiko Doi, Nozomi Fuse, Takayuki Yoshino, Kohei Shitara, Hideaki Bando, Hideaki Miyamoto, Susumu Koyama, Katsuya Tsukada, Atsushi Ohtsu. A phase I study of MEK inhibitor BAY 86-9766 in Japanese patients with advanced or reflactory solid tumors. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 27. doi:10.1158/1538-7445.AM2013-27

Clinical and biochemical spectrum of hypokalemic paralysis in North: East India

Background:Acute hypokalemic paralysis, characterized by acute flaccid paralysis is primarily a calcium channelopathy, but secondary causes like renal tubular acidosis (RTA), thyrotoxic periodic paralysis (TPP), primary hyperaldosteronism, Gitelman’s syndrome are also frequent.Objective:To study the etiology, varied presentations, and outcome after therapy of patients with hypokalemic paralysis.Materials And Methods:All patients who presented with acute flaccid paralysis with hypokalemia from October 2009 to September 2011 were included in the study. A detailed physical examination and laboratory tests including serum electrolytes, serum creatine phosphokinase (CPK), urine analysis, arterial blood gas analysis, thyroid hormones estimation, and electrocardiogram were carried out. Patients were further investigated for any secondary causes and treated with potassium supplementation.Result:The study included 56 patients aged 15-92 years (mean 36.76 ± 13.72), including 15 female patients. Twenty-four patients had hypokalemic paralysis due to secondary cause, which included 4 with distal RTA, 4 with Gitelman syndrome, 3 with TPP, 2 each with hypothyroidism, gastroenteritis, and Liddle’s syndrome, 1 primary hyperaldosteronism, 3 with alcoholism, and 1 with dengue fever. Two female patients were antinuclear antibody-positive. Eleven patient had atypical presentation (neck muscle weakness in 4, bladder involvement in 3, 1 each with finger drop and foot drop, tetany in 1, and calf hypertrophy in 1), and 2 patient had respiratory paralysis. Five patients had positive family history of similar illness. All patients improved dramatically with potassium supplementation.Conclusion:A high percentage (42.9%) of secondary cause for hypokalemic paralysis warrants that the underlying cause must be adequately addressed to prevent the persistence or recurrence of paralysis.

Myasthenia Gravis

Myasthenia gravis (MG) is the most common disorder of the neuromuscular junction (NMJ), with an estimated prevalence between 25 and 142 per million. It characteristically presents with fatigable weakness, often initially involving the ocular muscles and manifesting as intermittent ptosis and diplopia. Ultimately, the disease generalizes in two-thirds of patients, leading to weakness of bulbar, neck, limb, and respiratory muscles. The majority of patients with generalized MG, and roughly half of patients with purely ocular disease, harbor antibodies to skeletal muscle nicotinic acetylcholine receptors. A subset of patients with generalized disease have antibodies to muscle-specific receptor tyrosine kinase (MuSK). Acetylcholinesterase inhibitors are often the first modality of therapy for MG. As an immune-mediated disorder, MG can respond to several immunosuppressive agents, such as corticosteroids, azathioprine, mycophenolate mofetil, and cyclosporin. Thymectomy is a key component of management in appropriately chosen MG patients and those with thymoma. Newer or alternative immunotherapies including tacrolimus, rituximab, methotrexate, and complement inhibiting agents are an area of active investigation.

Dysphagia: The Common Thread in Two Uncommon Coexistent Conditions, Glomus Jugulare Tumor and Dysphagia Lusoria (P03.146)

Objective: To report a case of glomus jugulare tumor that was initially diagnosed as dysphagia lusoria. Background Glomus jugulare (GJ) tumors are very rare with an estimated incidence around one per 1.3 million people. Patients with GJ tumor usually present with conductive hearing loss and pulsatile tinnitus. Growth of the tumor can cause facial nerve paralysis, vertigo, hoarseness, and paralysis of lower cranial nerves. Active GJ tumors secrete catecholamines into the circulation. Patients with active GJ tumors have vasomotor symptoms like headaches, excess lacrimation and episodic flushing. Dysphagia is an uncommon presentation of GJ tumor (6%). Dysphagia lusoria due to compression of the esophagus by an aberrant subclavian artery is also uncommon with a prevalence of 0.5- 1.8%. Design/Methods: This is a case report from Yale-New Haven Hospital. Results: A 46-year-old female presented with progressive dysphagia with headaches and unilateral cranial nerve palsies demonstrating facial droop, tongue deviation and weakness of neck and shoulder muscles. Initial work up for her dysphagia revealed an aberrant right subclavian artery compressing the esophagus, so her symptoms were thought to be secondary to dysphagia lusoria. However, there was no relief of her dysphagia after the corrective surgery, and her headaches persisted. MRI of the brain was then done and revealed a GJ tumor. Octreotide scan depicted an octreotide-avid mass at the left jugular foramen consistent with a paraganglioma. Catecholamine assessments showed increased levels of epinephrine and normetanephrine in a 24 hour urine study. She underwent radiosurgical treatment with 16 Gy in a single fraction with improvement in her dysphagia. Conclusions: This case illustrates an unusual presentation of a rare catecholamine secreting GJ tumor (active type) causing dysphagia which initially mimicked dysphagia lusoria. This highlights the need to be vigilant in keeping a broad differential diagnosis in patients presenting with dysphagia. Disclosure: Dr. Mittal has nothing to disclose. Dr. Jabbari has nothing to disclose. Dr. Machado has nothing to disclose.

0906 A new clinical variant of the post-malaria neurological syndrome

Published cases of post-malaria neurological syndrome (PMNS) invariably report clinical and radiological encephalopathy. We report a case of brainstem and spinal cord inflammation without supratentorial involvement following recovery from Plasmodium...

Upper Thoracic Myelopathy Caused by Delayed Neck Extensor Weakness in Myotonic Dystrophy

Myotonic dystrophy is the most common autosomal dominant myopathy in adults. Our patient, a 41 year-old female suffering from myotonic muscular dystrophy, developed upper thoracic myelopathy due to hypertrophy of the ligamentum flavum and the posterior longitudinal ligament. She had a typical hatchet face and ptosis with "head hanging forward" appearance caused by neck weakness. Motor weakness, sensory changes and severe pain below T4 level, along with urinary incontinence began 3 months ago. Genetic and electrodiagnostic studies revealed myotonic dystrophy type 1. Magnetic resonance imaging of the spine showed loss of cervical lordosis and spinal cord compression due to hypertrophied ligamentum flavum and posterior longitudinal ligament at T1 to T3 level. We concluded that her upper thoracic myelopathy was likely related to the thickness of the ligamentum flavum and posterior longitudinal ligament due to repetitive mechanical stress on her neck caused by neck muscle weakness with myotonic dystrophy.

Clinical predictors of mechanical ventilation in Guillain-Barré syndrome

Patients with Guillain-Barré syndrome (GBS) require assisted ventilation frequently. However, no single factor can predict ventilator requirement. To identify clinical variables which could predict the need for mechanical ventilation in GBS. Tertiary hospital-based retrospective and prospective study. One hundred and thirty-eight GBS patients studied were divided into two groups ventilated (Group 1) and non-ventilated (Group 2). Parameters assessed included age, gender, associated illness(es), antecedent events, first symptom at onset, time from onset to bulbar involvement, confinement to bed and peak disability, upper limb power and reflexes at nadir, presence of facial weakness, neck muscle weakness and autonomic dysfunction. Multivariate predictors of ventilation were assessed using logistic regression analysis. There were 53 patients in Group 1 and 85 in Group 2. The mean age in the two groups was comparable. On bivariate analysis, simultaneous weakness of upper (UL) and lower (LL) limbs as the initial symptom (P<0.001); UL power less than Grade 3/5 at nadir (P<0.001); presence of neck and bulbar weakness (P<0.001); shorter duration from onset to bulbar weakness and confinement to bed (P=0.001) and bilateral facial involvement (P<0.01) were more frequently associated with the need for ventilation. Preserved reflexes in UL at nadir was significantly associated with absence of the need for mechanical ventilation (P<0.01). On multivariate analysis, factors independently associated with the need for mechanical ventilation included simultaneous motor weakness in UL and LL as the initial symptom (P=0.02), UL power<3/5 (Medical Research Council grade) at nadir (P=0.013) and presence of bulbar weakness (P<0.001). Preserved reflexes in the UL at nadir was independently associated with a lesser need for ventilation (P=0.001). Comprehensive assessment of clinical features may predict the need for mechanical ventilation in patients of GBS.

Gitelman syndrome: novel mutation and long-term follow-up

We report a case of Gitelman syndrome presenting with fatigue, paresthesias, weakness of limbs and neck muscles since 2.5years of age. Investigations showed hypokalemia and hypomagnesemia with urinary magnesium wasting. Genetic analysis revealed the presence of a novel homozygous mutation in the SLC12A3 gene (c.2879_2883+9ins14bp, p.Val 960 Glu fsx12). Management with potassium and magnesium supplements and spironolactone resulted in a significant improvement in symptoms. Over a follow-up of 11years, the patient showed satisfactory growth and physical development.

Hepatocellular carcinoma presenting as polymyositis: a paraneoplastic syndrome

Polymyositis as a paraneoplastic syndrome associated with hepatocellular carcinoma is quite rare; only a few cases have been reported. We report a case of a 50-year-old female who presented with subacute quadriparesis, neck muscle weakness, elevated creatinine phosphokinase, a myogenic pattern on the EMG and was diagnosed as having polymyositis, a paraneoplastic syndrome associated with hepatocellular carcinoma with negative hepatic viral markers and a positive ANA. Improvement in patient symptoms and areduction in creatinine phosphokinase, which occurred after lobectomy, supports this rare association.

Progressive Muscle Atrophy and Weakness After Treatment by Mantle Field Radiotherapy in Hodgkin Lymphoma Survivors

To describe the damage to the muscles and propose a pathophysiologic mechanism for muscle atrophy and weakness after mantle field radiotherapy in Hodgkin lymphoma (HL) survivors. We examined 12 patients treated by mantle field radiotherapy between 1969 and 1998. Besides evaluation of their symptoms, the following tests were performed: dynamometry; ultrasound of the sternocleidomastoid, biceps, and antebrachial flexor muscles; and needle electromyography of the neck, deltoid, and ultrasonographically affected arm muscles. Ten patients (83%) experienced neck complaints, mostly pain and muscle weakness. On clinical examination, neck flexors were more often affected than neck extensors. On ultrasound, the sternocleidomastoid was severely atrophic in 8 patients, but abnormal echo intensity was seen in only 3 patients. Electromyography of the neck muscles showed mostly myogenic changes, whereas the deltoid, biceps, and antebrachial flexor muscles seemed to have mostly neurogenic damage. Many patients previously treated by mantle field radiotherapy develop severe atrophy and weakness of the neck muscles. Neck muscles within the radiation field show mostly myogenic damage, and muscles outside the mantle field show mostly neurogenic damage. The discrepancy between echo intensity and atrophy suggests that muscle damage is most likely caused by an extrinsic factor such as progressive microvascular fibrosis. This is also presumed to cause damage to nerves within the radiated field, resulting in neurogenic damage of the deltoid and arm muscles.

P1.34 A novel homozygous mutation of the selenoprotein gene causes rigid spine syndrome with muscular dystrophy

Mutations of the selenoprotein gene (SEPN1) cause SEPN1-related myopathy which shares common clinical features characterized by severe weakness and wasting of neck and trunk muscles. SEPN1-related myopathy presents with early-onset and autosomal recessive inheritance. Here we describe a case with rigid spine syndrome due to a novel homozygous SEPN1 mutation.