Myotonic Dystrophy Type 1 Associating Sensitive Polyneuropathy: a Case Report

1 2nd Compartment of Neurology, Clinic of Neurology, Colentina Clinical Hospital, Bucharest, Romania 2 Faculty of Dental Medicine, „Carol Davila” University of Medicine and Pharmacy, Bucharest, Romania 3 Clinic of Pathology, Colentina Clinical Hospital, Bucharest, Romania 4 6th Department of Clinical Neuroscience, Clinic of Neurology, Colentina Clinical Hospital, „Carol Davila” University of Medicine and Pharmacy, Bucharest, Romania 5 Laboratory of Molecular Medicine, „Victor Babes” National Institute of Pathology, Bucharest, Romania Corresponding author: Elena Florentina MARINGICA, 2nd Compartment of Neurology, Clinic of Neurology, Colentina Clinical Hospital, Bucharest, Romania. E-mail: elena.maringica@gmail.com Abstract

Electrocardiogram, echocardiography and spirometry had normal results.
Nerve conduction studies revealed normal motor conduction and mild sensitive axonal neuropathy of the lower limbs ( Figure 1).
Electromyography identifi ed myopathic pattern in all examined muscles groups ( Figure 2) and myotonic discharges in the left tibialis anterior muscle and fl exor carpi ulnaris ( Figure 3).
Considering the clinical evolution, neurological examination and paraclinical investigations, the working diagnosis was muscular dystrophy.
We performed an open biopsy from the left gastrocnemius muscle under local anaesthesia. Th e muscle sample was snap frozen in liquid nitrogen cooled isopentane. Following the muscle orientation, transverse 8 microns thickness cryosections were obtained and stained for examination with standard histology and histochemistry techniques (hematoxylin and eosin HE, Van Gieson, modifi ed Gomori trichrome GT, Sudan BB, periodic acid -Schiff -PAS) and enzyme histochemical preparation for reduced nicotinamide adenine dinucleotide-tetrazolium reductase (NADH-TR), succinic dehydrogenase (SDH), lactic dehydrogenase (LDH), myosin adenosine triphosphatase (AT-Pase) with preincubation at pH 9.4, 4.63 and 4.35.

INTRODUCTION
Myotonic dystrophy is a multisystemic autosomal dominant disorder with chronic progression, characterized by aff ecting the skeletal muscles, ocular lens, heart, lungs, gastrointestinal tract, endocrine glands and central nervous system. Th e most common manifestations of DM are myotonia, weakness and muscular atrophy. Poor sleep quality, exhaustion and drowsiness have an important eff ect on the quality of life of these patients. In diff erent studies, the DM mortality rate is estimated 7.3 times higher than that of the normal population, and the average death was 53 years old in one 10-year follow-up study. Most of the cases of mortality in DM are correlated with cardiorespiratory disorders and it is considered that periodically follow-up reduces morbidity and mortality, even though there is no diseasemodifying therapy available [1][2][3][4][5]11 .
DM is an autosomal dominant neuromuscular disease caused by microsatellite expansions. Th ere are two types: DM type 1 (Steinert disease) and DM type 2 (Proximal Myotonic Myopathy -PROMM). DM type 1 is caused by expansion of CTG triplet repeat in the dystrophia myotonica protein kinase (DMPK) gene on chromosome 19q13.3. DM type 2 is caused by the expansion of a CCTG tetramer repeat in ZNF9 (CNBP) gene [1][2][3][4][5] . We report here the case of a 36-year old male diagnosed with DM type 1, who associated sensitive axonal polyneuropathy of the lower limbs. Th e confi rmation of the diagnosis of DM 1 was made by genetic testing.
Furthermore, it was considered necessary to make genetic testing -the relevant region of DMPK gene was analysed by polymerase chain reaction (PCR) and capillary electrophoresis on a DNA sequencing system for an expansion of the CTG trinucleotide repeat region. To exclude large expansions that cannot be identifi ed by standard fragment length analysis a triplet repeat primed PCR (TP-PCR) was carried out. Th e TP-PCR revealed a large CTG trinucleotide repeat expansion >50 repeats in the second allele. Th e result Th e skeletal muscle fragment presented well preserved architecture, marked variation in myofi ber size, some groups of 2-8 muscular fi bers with moderate and severe atrophy, many fi bers with one or more internal nuclei, especially the atrophic fi bers. Type 1 fi bers atrophy and type 2 fi bers hypertrophy is observed. Internal structure of the fi bers is normal (Figure 4, Figure 5.1-5.2). In conclusion, the morphological muscular changes are compatible, in the clinical and paraclinical context, with myotonic dystrophy type 1.   Th e patient was treated with vitamins B1, B6 and B12, intramuscular administration -1 vial/ day for 1 week, then 1 vial/week for 2-5 weeks, then 1 vial/ month until vitamin B12 seric level would have normalised and the patient was recommended to wear of the genetic analysis was consistent with DM type 1, so the patient was diagnosed with myotonic dystrophy type 1 (Steinert disease).
Also, an ophthalmologic evaluation documented the diagnosis of both eyes cataracts.    Developmental cognitive delay could occur; in later adult life, some patients tend to be skeptical, inattentive or argumentative 1,5 .
Diagnosis of DM type 1 is determined by clinical manifestations, family history, electromyography, muscle biopsy, but genetic testing remains the gold standard [1][2][3] . In this case report, the patient presented skeletal distal weakness but also sensitive polyneuropathy which initially obscured diagnosis. Th e etiology of the sensitive polyneuropathy could have been the B12 vitamin defi ciency or the interferon administration for hepatitis B virus infection. Furthermore, the patient was directed to the Hematology Department for complete Biermer anemia evaluation (peripheral blood smear, folate acid level dosing, autoantibodies to intrinsic factor, response to B12 vitamin replacement, superior digestive endoscopy with gastric mucosa biopsy).
Otherwise, peripheral nerve involvement may be one of the multisystemic manifestations of DM type 1, but is usually subclinical and independent of glucose intolerance (the presence of diabetes was not related to abnormal nerve conduction). Some studies sustain that most abnormal ENG results in DM type 1 patients are more likely to result from myopathic changes, coincidental neuropathies or radiculopathies than from primary involvement of the nerve 8,9 . In the diff erential diagnosis of DM type 1, it is essential to exclude other non dystrophic myopathies as myotonia congenita (which is typically associated with hypermyotrophy), hyperkalemic periodic paralysis, paramyotonia, adult-onset acid maltase deficiency or chronic denervating disorders, polymyositis, inclusion body myositis, toxic myopathies (associated with statins, clofi brate, chloroquine, colchicine) or distal myopathies (without myotonia) such as hereditary inclusion body myopathy, Welander distal myopathy or limb-girdle muscular dystrophy types 2B and 2L. Th ese disorders can be distinguished from DM by clinical manifestations, muscle biopsy results and genetic analysis 2,5 .
Th e patient presented in this case report was suspected of DM regarding the clinical presentation, the physical examination fi ndings and the results of the EMG and muscular biopsy, but the diagnosis of DM type 1 was confi rmed by the genetic testing.
Most patients with DM may need cardiac evaluations for arrhythmia and cardiomyopathy, spirometry, polysomnography, ophthalmologic examination for cataracts, swallowing assessment and endocrine testing 2,3,5 . molded ankle-foot orthoses to prevent foot-drop and enhance gait stability. Over a 6-month follow-up period, the patient experienced a light improvement in muscular function, at the physical examination the tendon refl exes were diminished, the B12 vitamin blood level was normal and the electroneurography showed physiological motor and sensitive conduction.

DISCUSSION
DM type 1 is the most common hereditary neuromuscular disorder among European adults. It is characterized by skeletal and smooth muscle aff ection, with progressive myopathy, myotonia and the involvement of multiple organs, as the endocrine glands and central nervous system. Th e pathogenesis of DM type 1 is considered to be produced by the expansion of the CTG trinucleotidic repeat in the DMPK gene (chromosome 19). Th e CTG triplet repeat expansion in the DMPK gene could determine nuclear localization of mutant mRNA. Toxic repeat RNA sequences could be responsible for the alteration of the normal expression of genes and the splicing process and may determine the abnormal expression of neuromuscular proteins. Clinical manifestations can be myotonia, skeletal and respiratory weakness, hypotrophia, cardiac arrhythmias, cataracts and insulin resistance [1][2][3][4][5] . DM 1 is classifi ed into four phenotypes: congenital, childhood, adult and mild phenotypes. Th e prognosis of DM type 1 is correlated with the age of onset. Patients with childhood-onset DM have higher mortality proportions, while patients with adult-onset DM typically have a more favorable prognosis. Adult-onset DM type 1 is the most prevalent form of DM 1. Th e main clinical manifestations include muscle weakness, myotonia and hypotrophia of the skeletal muscles. Most patients present myotonia, clinically manifest as a diffi culty in actively relaxing the thumb or fi ngers after active contraction. Th e hypotrophia initially aff ects the hand and the forearm muscles and then progresses to the head and facial muscles. Myotonia can be present simultaneously with hypotrophia or can precede it by a few years [1][2][3][4][5] .
Only symptomatic therapies are available for patients with DM type 1. For patients accusing severe myotonia, therapy with mexiletine 450 or 600 mg daily should be administered. Cardiac and respiratory dysfunctions are the most important causes of mortality in patients with DM type 1, therefore periodically cardiologic evaluation and spirometry must be performed. Associated cataracts treatment is surgical. 2,3,5,10 Development in the studying of the molecular mechanisms in the pathophysiology of myotonic dystrophy have brought to light possible new gene therapies to manage genetic disorders like dystrophic myotonia 5,10 .