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Psychomotor retardation due to spinal amyotrophy

Short summary

10 months old, female. After normal birth (at the 40th week of pregnancy) and neonatal period, started to suffer from gastroesophageal reflux and recurrent respiratory infections, at times with broncospasm. In addition, psychomotor retardation was found and the young patient was assessed by a neurologist. The tests run (EMG and genetics for SMA) pointed to the diagnosis of Spinal Amyotrophy.
After hospitalization due to catarrhal bronchitis, the patient was discharged in good general conditions with recomendations for respiratory physiotherapy and neurological rehabilitation.

Patient's questions

1) What therapy do you recommend?
2) Any treatments under trial?
3) Prognosis?
4) Is there a center of excellence in Italy?

Medical Background

10 months old, female.

Born at the 40th week of pregnancy by induced spontaneous delivery. Apgar 9/10. Weight at birth 3530 g. Physiological neonatal period. Exclusive breastfeeding until 4 months of age, then mixed from the 4th month on with extensive protein hydrolysate due to onset of atopic eczema for suspected CMPI (cow’s milk protein intolerance). Weaned at around 6-7 months with diet without milk and byproducts. She received the vaccinations required by law. She has undergone intermittent pharmacological treatment with Ranitidine since approximately the age of 3 months for suspected gastroesophageal reflux. This is why the child is followed on a regular basis at the pediatric gastroenterology outpatient clinic.

In pathological clinical history, recurring respiratory infections, at times with broncospasm, treated orally with antibiotics at home, are noted. Hospitalization for gastroenteritis and asthmatic bronchitis.

After finding psychomotor retardation, the young patient was assessed by a neurologist. The tests run (EMG and genetics for SMA) pointed to a homozygote delection of the exons examined (7 and 8) of the SMN1 gene, findings compatible with the diagnosis of Spinal Amyotrophy.
Due to the onset of a slight fever and persistent catarrhal coughing, the child was taken to the pediatric emergency room, where chest X-rays were taken (incomplete expansion of the pulmonary fields, increased pulmonary markings in the bilateral hilar-perihilar region slightly more evident in the inferior horns, no signs of pleural effusion,cardiac image with size apparently within the normal limits), blood tests (GB 8300/mmc, GN 52.5%, L 42.1%, M 5%, PCR 0.27 mg/dl) and she was hospitalized for treatment and further tests.

At the neurological examination: “overall conditions satisfactory, lively and reactive. Weight: 8.330 kg. Heart, chest and abdomen: no abnormality detected. Reported is hypotone of the lower limbs with distal and proximal hyposthenia. No complete control of the trunk. Good control of the head”.
The young patient was discharged in good general conditions with the diagnosis of “catarrhal bronchitis in child suffering from Spinal Amyotrophy”. She must start respiratory physiotherapy and neurological rehabilitation shortly.

Medical opinion

1) What therapy do you recommend?
This is an excellent published resource to access:Consensus Statement for Standard of Care in Spinal Muscular Atrophy Ching H. Wang, Richard S. Finkel, Enrico S. Bertini, Mary Schroth, Anita Simonds, Brenda Wong, Annie Aloysius, Leslie Morrison, Marion Main, Thomas O. Crawford, Anthony Trela and Participants of the International Conference J Child Neurol 2007; 22; 1027 .

Growth curves are very important to track. Given the history of feeding difficulties, I would suspect the patient will be falling or has fallen off growth curves: weight and length for age. Pediatric and SMA experienced dietician is of great value to optimize food choices and help family set up nutritional goals.
Depending on parent wishes, resources and understanding of risk:benefit, consideration of gastrostomy tube is of value to ensure adequate nutrition which could be night-time drip feeds. Will be important to do barium swallow to see if reflux is of enough significance to warrant Nissen fundoplication. Aspiration pneumonia can be life-threatening. If reflux is not as worrisome, may continue oral feeds as tolerated which usually is not adequate for total nutritional needs.
Aggressive pulmonary care is essential including BiPap to help enable rib cage expansion and lung tissue growth in proportion to body. If pulmonary issues are not targeted then the rib cage and lungs do not grow in proportion and the child will be at large risk of pneumonia. When older a cough assist device is of great value to clear secretions and expand lung tissue to prevent atelectacsis.
Influenza and pneumovac immunizations are of great value
Parental counseling for patient's parents is that future children will have 25% chance of recurrence for SMA as well as 50% chance that any future children will be carriers. Presumably each parent is a carrier which is very common - SMA has a carrier frequency of 1:33–1:60 in most populations. Wilson and Ogino The Lancet, Volume 372, Issue 9649, Page 1542, 1 November 2008.

2) Any treatments under trial?
These interventions are being tested in trials but none have had huge effects in SMA type I. Future molecular medicine research including IGF1 and other gene therapy’s efforts may be realized in the not so distant future.
Carnitine and valproic acid Swoboda K et al. PloS One (2009) 4(5):1-9 .
Hydroxyurea Laing W et al. Journal of the Neurological Sciences 268 (2008) 87–94 .
Salbutamol in type II SMA M Pane et al. Neuromuscular Disorders 18 (2008) 536–540 .
Albuterol M. Kinali et al. Neurology 2002;59;609-610 .

3) Prognosis?
Seems consistent with SMA type 1 based on age of presentation and lack of sitting (so far). Some physical exam features mentioned including psychomotor retardation, heart, chest and abdomen: no abnormality detected. Reported is "hypotone of the lower limbs with distal and proximal hyposthenia. No complete control of the trunk. Good control of the head”.
Scant muscle bulk, bright eyes, tongue fasciculations, areflexia, bell-shape chest would be typical for type I SMA.
Good head control would be unusual for SMA type? Please clarify
No complete control of the trunk? If I am interpreting this correctly, the child has poor trunk control much like a rag doll?
Would recommend ordering blood DNA gene dosage of SMN2 gene which can enhance prognostic assessment – if 3 or more copies, can mean more favorable outcome. If only 1-2 copies, less favorable.
EMG/NCV ulnar CMAP (if >0.8 mV) has prognostic value as well.
Natural history of untreated SMA type I is typically death by 2 years of age. Aggressive pulmonary and nutritional interventions can alter the natural history with obvious dependence on medical assistive devices.

4) Is there a center of excellence in Italy?
It is of great value to find a center of excellence with SMA type I expertise. Seems there are at least 2 if not 3 excellent options in Italy.
FTELE is a major Italian non-profit foundation, raising and distributing funds to advance scientific research towards the cure for muscular dystrophy and other genetic diseases. FTELE has created and manages four research Institutes (intramural research): the FTELE Institute of Genetics and Medicine, devoted to the identification of genes responsible for genetic diseases and their functions; the HSR-Telethon Institute of Gene Therapy whose research is focused on the development of gene therapy protocols for inherited diseases; the Dulbecco FTELE Institute aimed at helping Italian scientists with excellent CVs to return and work successfully in Italy; Tecnothon, which carries out research into creating technical aids for the disabled. FTELE runs also collaborative programs with other international funding agencies: AFM (Association Française contre les Myopathies) and JDRF (Juvenile Diabetes Research Foundation).
Within the field of neuromuscular disease, FTELE supports preclinical projects aimed at developing cutting edge treatments (pharmacological, stem cells, and gene therapy projects), clinical studies aimed at developing clinical, diagnostic and therapeutic tools, outcome measures, databases, databases, and muscle biobanks. FTELE is a member of the Working Group for Biobank Certification of the National Committee for Biosafety and Biotechnology, and the European Neuromuscular Centre. FTELE participates in the International Trial on Steroids in DMD, coordinating the Italian Clinical Centres involved in the study.

Laboratory of Molecular Medicine, Bambino Gesu’ Children’s Research Hospital (OBG)
The Unit of Molecular Medicine is located at the Bambino Gesù Children’s Research Institute in Rome (Italy), and is a national referring center in Italy for a large number of pediatric diseases, including muscular and neuro-degenerative disorders. The Unit is a European referring center for molecular diagnosis of some rare disorders, and in the standardisation committees to design trials in Spinal Muscular Atrophy.

Università Cattolica Sacro Cuore
UCSC has a long standing experience with neuromuscular disorders. Several members of the Institute of Neurology and of the Institute of Genetics of the UCSC have been coordinating national networks for classification, definition of outcome measures and therapeutical trials in neuromuscular disorders and are part of international clinical networks. The UCSC is currently involved, in collaboration with several centres from Europe and USA, in the definition of outcome measures for spinal muscular atrophy (SMA) and Duchenne muscular dystrophy (DMD). UCSC has coordinated a multicentric study using phenylbutyrrhate in SMA and is also involved in the international trial on the use of steroids in DMD. UCSC is implicated in the USA standards of care committee for Spinal muscular atrophies, the Families of SMA, the Parent Project and the Telethon (IT).

Neuromuscular & Molecular-Genetic Unit of the University of Ferrara (UNIFE)
The Unit of Molecular Medicine has been recently integrated into the Neuromuscular Unit formerly active at the Rizzoli’s Institute in Bologna. The Neuromuscular Unit has a longstanding tradition of experience in the diagnosis and rehabilitation of childhood and adult neuromuscular conditions including in particular SMA, DMD, and CMD. The Molecular Genetics laboratory has been recognised as “excellent centre” in the Regione Emilia Romagna and the strength of the unit is the large critical mass of patients, the molecular diagnostic expertise together with an active program of research and key national and international collaborations. The laboratory has been founded with several national and international grants focused on dystrophinopathies. The UNIFE could provide interface of the TREAT-NMD NoE with the Italian patients association (Duchenne Parent Project Italy and UILDM).

Italian Fondazione Telethon

Anna Ambrosini - Research Program Manager
Anna Ambrosini (PhD in Pharmacology and Toxicology): 15 years experience in research laboratories active in the field of neuroscience. Since 2001 is Research Program Manager for the Italian Fondazione Telethon, where, in particular, she is responsible for developing programs in the field of inherited neuromuscular diseases.
She is highly involved at national level in new initiatives developed with a number of Italian neuromuscular Patients’ Associations as part of a NMD Alliance and she is coordinating the activity of the Italian NMD clinical network as FTELE partner of TREAT-NMD.
She is member of the Steering Committee for the International Trial on Steroids in DMD (FOR-DMD study).
Since April 2009 she is the Chair of the Executive Committee of the European NeuroMuscular Centre (ENMC) Consortium, where she represents Fondazione Telethon and the Italian Muscular Dystrophy Association (UILDM).
Enrico Bertini - Neurologist 
leading the Unit of Molecular Medicine, the section on Morphology, and the Neuromuscular Clinics. Published more than 163 index papers. Is involved in the standardisation committees to design trials in Spinal Muscular Atrophy, and in the diagnosis of Congenital Muscular Dystrophies.
Eugenio Mercuri Md PhD (Associate Professor in Pediatric Neurology, Catholic University Rome):
areas of expertise: congenital muscular dystrophy, outcome measures and assessment tools in neuromuscular disorders. Publications: over 130 publications on various topics related to paediatric neurology and neuromuscular disorders.
Sonia Messina, MD and PhD - Neurologist areas of expertise:
congenital muscular dystrophy, outcome measures and assessment tools in neuromuscular disorders. Over 40 publications on various topics related to neuromuscular disorders and paediatric neurology. 
Luciano Merlini MD (Neurologist):
Formerly chief of the Neuromuscular Unit of the IOR, Bologna, now works as neuromuscular consultant in the Medical Genetic Unit of the University of Ferrara. Scientific Manager of the Myo-cluster (EU FP5 Contract N° QLG1-CT-1999-00870), a cluster of European myology research groups. PI of 2 SMA randomized clinical trials: Italian SMART with gabapentin, and EuroSMART with acetyl-L-carnitine. Planning a pilot trial in Ullrich congenital muscular dystrophy with CsA. Executive board officer of the World Muscle Society (WMS) and the Italian Association of Myology (AIM). Associate Editor of Neuromuscular Disorders, the official journal of WMS. Chairman in several ENMC workshop. More than 130 publications on the topic of myology in the last 10 years. Particular interests in NMD: muscle strength evaluation, clinical trial design, rehabilitation.