Three years pilot of spinal muscular atrophy newborn screening turned into official program in Southern Belgium.

Three new therapies for spinal muscular atrophy (SMA) have been approved by the United States Food and Drug Administration and the European Medicines Agency since 2016. Although these new therapies improve the quality of life of patients who are symptomatic at first treatment, administration before the onset of symptoms is significantly more effective. As a consequence, newborn screening programs have been initiated in several countries. In 2018, we launched a 3-year pilot program to screen newborns for SMA in the Belgian region of Liège. This program was rapidly expanding to all of Southern Belgium, a region of approximately 55,000 births annually. During the pilot program, 136,339 neonates were tested for deletion of exon 7 of SMN1, the most common cause of SMA. Nine SMA cases with homozygous deletion were identified through this screen. Another patient was identified after presenting with symptoms and was shown to be heterozygous for the SMN1 exon 7 deletion and a point mutation on the opposite allele. These ten patients were treated. The pilot program has now successfully transitioned into the official neonatal screening program in Southern Belgium. The lessons learned during implementation of this pilot program are reported.

Intrathecal nusinersen treatment for SMA in a dedicated neuromuscular clinic: an example of multidisciplinary and integrated care.

Nusinsersen is now available in Italy for all SMA types. We describe the experience with intrathecal treatment with nusinersen in 50 patients with SMA at the NEMO Center (NEuroMuscular Omniservice Clinical Center) in Milan, a neuromuscular patient-centered clinic hosted within Niguarda Hospital, a National Public General Hospital. Our results indicate that the pathway of care described outweighs the burden due to the repeated intrathecal injections. Irrespective of age and severity, the treatment is feasible, accessible, and replicable provided that there is a multidisciplinary team having experience and training in SMA.

Utility of repetitive nerve stimulation test for ALS diagnosis.

OBJECTIVE: Decremental responses in the repetitive nerve stimulation (RNS) test in amyotrophic lateral sclerosis (ALS) patients have been reported, although their possible diagnostic role has received little investigation. We investigated their diagnostic role in differentiation between ALS and cervical spondylotic amyotrophy (CSA), an important ALS mimic especially in Japan. METHODS: Patients were prospectively enrolled and the diagnosis was confirmed by follow-up. RNS was performed on the abductor pollicis brevis (APB), upper trapezius (trapezius) and deltoid muscles. RESULTS: Enrolled subjects consisted of 53 ALS and 37 CSA patients. Abnormal decremental responses (>5%) were observed in 32%, 51% and 75% of ALS patients and 3%, 0% and 20% of CSA patients for the APB, trapezius and deltoid muscles, respectively. The sensitivity for 23 ALS patients with upper-limb onset was 78% for the trapezius and 100% for the deltoid muscles. CONCLUSIONS: An abnormal decremental response in the trapezius muscle was 100% specific to ALS in comparison with CSA: abnormal decrement in this muscle would strongly suggest ALS. No decrement in the deltoid muscle might exclude ALS in patients having symptoms with upper-limb onset. SIGNIFICANCE: RNS is useful in differentiation between ALS and CSA.

Impact of fetal or child loss on parents' perceptions of non-invasive prenatal diagnosis for autosomal recessive conditions.

OBJECTIVE: to explore parents' personal attitudes towards non-invasive prenatal diagnosis in the context of their own experiences caring for a child affected with a genetic condition or after the loss of a fetus, infant, or child due to the condition. METHODS: we collected in-depth data from parents via either focus groups or individual interviews. DESIGN: this was a cross-sectional interpretive study based on grounded theory. SETTING: United Kingdom. PARTICIPANTS: 17 parents (13 women and four men) who were carriers of a serious autosomal recessive condition: spinal muscular atrophy, cystic fibrosis or thalassaemia. All had a child (living or deceased) with the condition. FINDINGS: parents experienced changes in reproductive self-identity due to their experiences of having an affected child: this influenced their views of non-invasive prenatal testing. They began their reproductive journeys 'naively', but described feelings of reproductive vulnerability after the diagnosis of the child and consequent realisation of risks to future children. They viewed non-invasive prenatal testing as a way to reduce threats to unborn children, while allowing prenatal diagnosis. KEY CONCLUSIONS: when parents lose a child they may use emotional guarding, delayed pregnancy disclosure and avoidance of harmful activities to cope in future pregnancies. Parents who want to consider early prenatal testing are less able to utilise these strategies, but non-invasive methods allow them to reduce the risk. IMPLICATIONS FOR PRACTICE: midwives should be sensitive to parents' reproductive vulnerability after genetic diagnosis of a child and ensure they are supported to consider the option of non-invasive prenatal testing if appropriate.

Substrate reduction therapy with miglustat in chronic GM2 gangliosidosis type Sandhoff: results of a 3-year follow-up.

GM2 gangliosidosis type Sandhoff is caused by a defect of beta-hexosaminidase, an enzyme involved in the catabolism of gangliosides. It has been proposed that substrate reduction therapy using N-butyl-deoxynojirimycin (miglustat) may delay neurological progression, at least in late-onset forms of GM2 gangliosidosis. We report the results of a 3-year treatment with miglustat (100 mg t.i.d) in a patient with chronic Sandhoff disease manifesting with an atypical, spinal muscular atrophy phenotype. The follow-up included serial neurological examinations, blood tests, abdominal ultrasound, and neurophysiologic, cognitive, brain, and muscle MRI studies. We document some minor effects on neurological progression in chronic Sandhoff disease by miglustat treatment, confirming the necessity of phase II therapeutic trials including early-stage patients in order to assess its putative efficacy in chronic Sandhoff disease.

Carrier frequency of SMA by quantitative analysis of the SMN1 deletion in the Iranian population.

BACKGROUND AND PURPOSE: Spinal muscular atrophy (SMA) is a common autosomal recessive neuromuscular disorder. Carrier frequency studies of SMA have been reported for various populations. Although no large-scale population-based studies of SMA have been performed in Iran, previous estimates have indicated that the incidence of autosomal recessive disorder partly because of the high prevalence of consanguineous marriage is much higher in the Iranian population than in other populations. METHODS: In this study, we used a reliable and highly sensitive quantitative real-time PCR assay with SYBR green I dye to detect the copy number of the SMN1 gene to determine the carrier frequency of SMA in 200 healthy unrelated, non-consanguineous couples from different part of Iran. RESULTS: To validate the method in our samples, we determined the relative quantification (RQ) of patients with homozygous deletion (0.00) and hemyzygous carriers (0.29-0.55). The RQ in 10 of 200 normal individuals were within the carrier range of 0.31-0.57, estimating a carrier frequency of 5% in the Iranian population. CONCLUSIONS: Our data show that the SMA carrier frequency in Iran is higher than in the European population and that further programs of population carrier detection and prenatal testing should be implemented.

Multimodal evoked potentials of Kennedy's disease.

BACKGROUND: Kennedy's disease (KD) is an X-linked recessive polyglutamine disease. Traditionally, it is a lower motor neuron syndrome with additional features such as gynecomastia and tremor. Sensory symptoms are minimal if ever present. We used multimodal evoked potential (EPs) tests to study the distribution of the involvement of the disease. METHODS: Visual, brainstem auditory, somatosensory and motor EPs were studied in six KD patients. All of them had typical presentations and had been proved genetically. RESULTS: Abnormal findings were noted as follows: prolonged peak latencies of visual EPs, increased hearing threshold level, inconsistent brainstem auditory EPs, decreased amplitudes of cortical potentials of somatosensory EPs, and increased motor threshold to transcranial magnetic stimulation. CONCLUSIONS: Our multimodal EP studies showed that KD involved multiple levels of the nervous system. It implies the widespread effects of the mutant androgen receptors.

Establishing a standardized therapeutic testing protocol for spinal muscular atrophy.

Several mice models have been created for spinal muscular atrophy (SMA); however, there is still no standard preclinical testing system for the disease. We previously generated type III-specific SMA model mice, which might be suitable for use as a preclinical therapeutic testing system for SMA. To establish such a system and test its applicability, we first created a testing protocol and then applied it as a means to investigate the use of valproic acid (VPA) as a possible treatment for SMA. These SMA mice revealed tail/ear/foot deformity, muscle atrophy, poorer motor performances, smaller compound muscle action potential and lower spinal motoneuron density at the age of 9 to 12 months in comparison with age-matched wild-type littermate mice. In addition, VPA attenuates motoneuron death, increases spinal SMN protein level and partially normalizes motor function in SMA mice. These results suggest that the testing protocol developed here is well suited for use as a standardized preclinical therapeutic testing system for SMA.

Proton magnetic resonance spectroscopy in Kennedy syndrome.

OBJECTIVE: To seek regional metabolite abnormalities in patients with Kennedy disease (KD) using proton magnetic resonance spectroscopy. DESIGN: Nine patients with KD showing the typical phenotype without clinical signs of upper motor neuron involvement were compared with 17 male, age-matched, healthy control subjects. Relative metabolite concentrations for N-acetyl (NA) groups, choline-containing groups (Cho), phosphocreatine (Cr), and lactate (Lac) were determined in the brainstem and the motor region. RESULTS: Pathologic Lac signals suggesting impaired energy metabolism were absent in patients and controls. In the brainstem area, patients with KD showed a significant reduction in the NA/Cho metabolite ratio (P = .01). In the motor region, NA/Cho (P = .04) and NA/Cr (P = .03) ratios were significantly reduced. The reduction of the NA/Cho ratio in the motor region mainly resulted from decreased metabolite ratios in 3 patients. Changes in metabolite ratios did not correlate with the number of trinucleotide cytosine-adenine-guanine repeats from leukocytes. Because of the relatively small sample size due to the rarity of KD, these results should be considered preliminary. CONCLUSIONS: Spectroscopic data fail to provide further evidence for altered energy metabolism in KD. Metabolite changes in the brainstem indicate a reduction of the neuronal marker NA or elevated Cho. These findings may reflect neuronal loss or gliosis consistent with the known pathologic features. In a subset of patients, altered metabolite ratios best explained by neuronal loss suggest subclinical involvement of the motor region. The extent of metabolite changes does not correlate with the trinucleotide repeat length.

Quantification of brain metabolites in amyotrophic lateral sclerosis by localized proton magnetic resonance spectroscopy.

We performed proton magnetic resonance spectroscopy (1H-MRS) in patients with motor neuron disease (MND) to determine the absolute in vivo concentrations in the brain of the metabolites N-acetyl aspartate (NAA), choline (Cho), and creatine (Cr/PCr). We examined the spectra acquired from a 20 x 20 x 20-mm3 voxel placed in the motor cortex and in the cerebellum from seven patients with clinically probable or definite amyotrophic lateral sclerosis (ALS) according to the El Escorial criteria, from three patients with suspected ALS (progressive muscular atrophy), and from eight normal control subjects. We estimated the concentrations of the metabolites using the water signal as an internal standard. The concentrations of Cho and Cr/PCr in both brain regions, as well as the concentration of NAA in the cerebellum, were unaltered in the MND patients compared with the controls. Only MND patients with both upper and lower motor neuron signs had a significantly decreased concentration of NAA (9.13 +/- 0.28 mM, mean +/- SEM) in the primary motor cortex when compared with healthy controls (10.03 +/- 0.22 mM). In conclusion, the slightly decreased concentration of NAA in the primary motor cortex from ALS patients may represent a loss of neurons in this region.

Cervical radiculopathy: a case for ancillary therapies?

OBJECTIVE: To present two cases, one of a patient with a radicular syndrome and another of a patient with a pseudoradicular syndrome. CLINICAL FEATURES: A 45-yr-old man visited one chiropractic clinic complaining of a "pinched nerve" in his neck, with pain and paresthesia in his left hand. He reported that these symptoms began after a work accident 1 month before, when he lifted a heavy object. Radiographs revealed disk space thinning at C4-5, C5-6 and C6-7. CT scans revealed foraminal narrowing with a minor disk bulging at the level of C5-6 and a large disk protrusion at C7-T1. The second patient is a 60-yr-old man with left shoulder and cervical spine pain. The patient stated that the shoulder pain felt like an ache and had begun 2 wk earlier when he had awakened with pain in the shoulder and a stiff neck. X-ray evaluation revealed a moderate level of degenerative change at the the C4-5, C5-6 and C7-T1 region. CONCLUSION: This article identifies the similarities and variations between two syndromes receiving chiropractic intervention that included ancillary therapy. Certain conditions, including cervical radiculopathy, seem to respond well to chiropractic spinal manipulative therapy. However, in other conditions with similar symptomatology, appropriate referral may be necessary for the condition to respond. Alternatively, adjunctive or ancillary therapy may be indicated to improve the effect of the chiropractic intervention.

X-linked bulbospinomuscular atrophy (Kennedy's disease) masquerading as lead neuropathy.

A 43-year-old male was referred by a veterinarian who evaluated his dog for a seizure and suspected a toxic lead exposure for both. He refurbished houses, removing old paint, and complained of decreased cognition, fatigue, and muscle cramps. He had a depressed affect, postural tremor, right arm weakness with partial denervation on EMG, and borderline-low sensory nerve action potential (SNAP) amplitudes. A mild anemia and elevated serum and urine lead levels supported a diagnosis of lead neuropathy. Chelation therapy increased urine lead excretion without symptomatic improvement. His brother worked part-time with him and developed similar findings, but also had difficulty chewing, dysphagia, perioral twitching, gynecomastia, and multifocal denervation of extremity and facial muscles. His lead levels were not elevated, but an androgen receptor mutation identified on the X chromosome for both brothers confirmed the diagnosis of X-linked bulbospinomuscular atrophy (Kennedy's disease).