Neuromyelitis Optica in a Patient from Family with both Myotonic Dystrophy Type 1 and 2

Abstract

Introduction: The aim of this study was to present a family co-segregating myotonic dystrophy type 1 (DM1) and 2 (DM2), and one member affected with neuromyelitis optica (NMO).

Case report: Index case underwent cataract surgery at age 39. Although she had no muscle symptoms, genetic testing revealed a DM2 mutation and a DM1 protomutation. The patient noticed difficulties in climbing stairs at age 47. Clinical examination showed mild muscle weakness, calf hypertrophy, mild myotonia and several multisystem signs. Patient’s mother had DM1 protomutation and clinically exhibited only cataract. Two proband’s sisters, one with DM2 mutation and another with DM2 mutation and DM1 protomutation, had a clinical presentation similar to the index case. In addition, the latter also developed NMO.

Conclusion: Our findings suggest that screening for both DM1 and DM2 should be done and a positive result in either gene should not be an indication to stop screening, but to move to the other gene.

INTRODUCTION

Myotonic dystrophies are autosomal dominant diseases caused by CTG repeats in the DMPK gene in myotonic dystrophy type 1 (DM1), and CCTG repeats in the CNBP gene in myotonic dystrophy type 2 (DM2) [1]. Autoimmune diseases were found in 21% of DM2 patients versus 2% of DM1 [2]. Here we report the first family with both DM1 and DM2 in individual cases, with concomitant NMO in one of them.

CASES REPORT

Genetic pedigree of examined family is presented in Fig. 1. All patients signed informed consent. Proband case (II-7) underwent cataract surgery at age 39. Although she was free of muscle symptoms, blood was collected for genetic analysis. Expansions of CCTG and CTG repeats were detected (Fig. 1). At age 47 she noticed difficulties while climbing stairs and a year later she was hospitalized at the Neurology Clinic (Table 1).

Patient II-1 was negative for DM2 and had 59–64 CTG repeats in the DMPK gene. She refused to be clinically examined. Patient II-5 was negative for DM1 and positive for DM2 (130–1150 CCTG). She noticed difficulties while climbing stairs at age 47. She was clinically examined at age 51 (Table 1).

Patient II-3 was positive for both DM1 (65–70 CTG) and DM2 (100–1010 CCTG). She developed pain and weakness in proximal legs at age 47. At age 53, she had a severe left eye optic neuritis. She received methylprednisolone (1000 mg/day, five days) followed by prednisone tapering, but without improvement. Ten months later she had severe right eye optic neuritis treated with a short-course high-dose steroids, with no improvement. At age 54 she had severe bilateral visual loss with optic nerve atrophy (Table 1). Cerebrospinal fluid (CSF) glucose, proteins and cell count were normal. No CSF-specific immunoglobulin G bands were found. Prolonged corticosteroid therapy was introduced. After one month she developed paraplegia with decreased sensibility below the seventh thoracic level and inability to control sphincters, with spine MRI showing longitudinally extensive transverse myelitis (Th4-Th7). Antibodies against aquaporin 4 in serum were positive, confirming NMO. She was treated with high-dose methylprednisolone followed by steroid taper and with 11 therapeutic plasma exchange (TPE) procedures during 40 days. Azathioprine (150 mg daily) was also introduced. Slight improvement in flexion of the right foot and knee was observed, with no improvement in visual acuity.

Mother of patients (I-2) was examined at age 79. She had only eye cataract. She had 56–61 CTG repeats in the DMPK gene and was negative for CNBP mutation. Father of patients (I-1) passed away years ago. He had walking difficulties and eye cataract before age of 60.

Children of II-3 and II-5 patients, aged 16–27, were clinically and genetically examined after informed consent. Three of them inherited DM2 mutation and were free of symptoms.

Immunological screening was performed in patients I-2, II-5, II-7, III-3, III-4, III-6 and III-7. Neither of them fulfilled criteria for any immunological disease, although II-7 had mildly increased circulating immune complexes and antinuclear antibodies (Table 1).

DISCUSSION

This is the first report of patients with both DM1 and DM2 mutations. If prevalence for each of the diseases is 10 per 100000 [1], chance of concomitant expression seems to be 1 in 400000000. Our patients with both DM2 and DM1 did not differ in investigated clinical features compared to sister with only DM2. Only distal muscle weakness, typical for DM1, was more pronounced in patients with both mutations. Considering that DM2 and DM1 share common molecular mechanisms, our observation is in line with the report that phenotype is same in homozygous and heterozygous state of DM1 and DM2 mutation [3].

Although different autoimmune diseases were described in DM [2], case II-3 is the first one with NMO. This association is highly intriguing since AQP4 is expressed in the sarcolemma [4]. The potential mechanism of the secondary autoimmune activation against sarcolemmal AQP4 in the setting of the primary muscle degeneration and impaired RNA metabolism could be speculated. Reduced levels of IgG and IgM antibodies were previously described in both DM1 and DM2 patients, while autoimmune diseases and autoantibodies were more common in DM2 [2].

It seems that genetic screening for DM1 and DM2 may be beneficial in younger patients with cataract. Studies including cataract patients reported 2 out of 231 and 4 out of 274 patients with primary cataract of adult onset to have protomutation in the DMPK gene [5]. Similar study has not been performed for DM2 mutation so far.

We presented a family with an unusual genetic background. Our findings suggest that screening for both DM1 and DM2 should be done and a positive result in either gene should not be an indication to stop screening, but to move to the other gene. This might unmask additional patients with doublemutations.