Scholarly article on topic 'Respiratory and cardiac function in congenital muscular dystrophies with alpha dystroglycan deficiency'

Respiratory and cardiac function in congenital muscular dystrophies with alpha dystroglycan deficiency Academic research paper on "Clinical medicine"

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{"Congenital muscular dystrophy" / "Alpha dystroglycan" / Heart / Respiratory}

Abstract of research paper on Clinical medicine, author of scientific article — M. Pane, S. Messina, G. Vasco, A.R. Foley, L. Morandi, et al.

Abstract The aim of this retrospective study was to assess respiratory and cardiac function in a large cohort of patients with congenital muscular dystrophies (CMD) with reduced glycosylation of alphadystroglycan (α-DG). Thirteen of the 115 patients included in the study died between the age of 1month and 20years. The age at last follow up of the surviving 102 ranged between 1year and 68years (median: 9.3years). Cardiac involvement was found in 7 of the 115 (6%), 5 with dilated cardiomyopathy, 1 cardiac conductions defects and 1 mitral regurgitation. Respiratory function was impaired in 14 (12%). Ten of the 14 required non invasive nocturnal respiratory support, while the other four required invasive ventilation. Cardiac or respiratory involvement was found in patients with mutations in FKRP, POMT1, POMT2. All of the patients in whom mutation in POMGnT1 were identified had normal cardiac and respiratory function.

Academic research paper on topic "Respiratory and cardiac function in congenital muscular dystrophies with alpha dystroglycan deficiency"

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Neuromuscular Disorders 22 (2012) 685-689

www.elsevier.com/locate/nmd

Respiratory and cardiac function in congenital muscular dystrophies with alpha dystroglycan deficiency

M. Panea, S. Messinaa b, G. Vascoa, A.R. Foleyc, L. Morandid, E. Pegoraroe, T. Monginif, A. D'Amico g, F. Bianco a, M.E. Lombardoa, R. Scalisea, C. Bruno h, A. Berardinellii, A. Pinil, I. Moronid, M. Morad, A. Toscanob, M. Moggiom, G. Comim, F.M. Santorellig, E. Bertinig, F. Muntonic, E. Mercuria c *

a Department of Paediatric Neurology, Catholic University, Rome, Italy b Department of Neurosciences, Psychiatry and Anaesthesiology, University of Messina, Italy c Dubowitz Neuromuscular Centre, University College London Institute of Child Health and Great Ormond Street Hospital for Children,

London, United Kingdom

Myopathology and Neuroimmunolgy, Pediatric Neurology and Neuroradiology Units, Neurological Institute C. Besta, Milan, Italy e Department of Neurosciences and Psychiatry and Anaesthesiology, University of Padova, Italy Neuromuscular Center, S.G. Battista Hospital, University of Turin, Italy g Department of Laboratory Medicine, Unit of Molecular Medicine, Bambino Gesù Hospital, Rome, Italy h Neuromuscular Disease Unit, G. Gaslini Institute, Genoa, Italy ' IRCCS "C. Mondino" Foundation, University of Pavia, Italy l Child Neurology and Psychiatry Unit, Maggiore Hospital, Bologna, Italy m Dino Ferrari Center, Department of Neurological Science, University of Milan, Italy

Received 20 March 2012; received in revised form 1 May 2012; accepted 18 May 2012

Abstract

The aim of this retrospective study was to assess respiratory and cardiac function in a large cohort of patients with congenital muscular dystrophies (CMD) with reduced glycosylation of alphadystroglycan (a-DG). Thirteen of the 115 patients included in the study died between the age of 1 month and 20 years. The age at last follow up of the surviving 102 ranged between 1 year and 68 years (median: 9.3 years). Cardiac involvement was found in 7 of the 115 (6%), 5 with dilated cardiomyopathy, 1 cardiac conductions defects and 1 mitral regurgitation. Respiratory function was impaired in 14 (12%). Ten of the 14 required non invasive nocturnal respiratory support, while the other four required invasive ventilation. Cardiac or respiratory involvement was found in patients with mutations in FKRP, POMT1, POMT2. All of the patients in whom mutation in POMGnT1 were identified had normal cardiac and respiratory function. Published by Elsevier B.V.

Keywords: Congenital muscular dystrophy; Alpha dystroglycan; Heart; Respiratory

1. Introduction

The term "dystroglycanopathies" has been used to describe a genetically heterogeneous group of muscle disor-

* Corresponding author. Address: Department of Paediatric Neurology, Catholic University, Rome, Italy.

E-mail address: mercuri@rm.unicatt.it (E. Mercuri).

ders with a muscle biopsy showing dystrophic features and a reduction of a-dystroglycan (a-DG) with frequently associated central nervous system involvement [1].

The spectrum of clinical phenotypes ranges from the severe Walker-Warburg syndrome (WWS), muscle-eye-brain disease (MEB) and Fukuyama congenital muscular dystrophy (FCMD), all with severe muscle, eye and brain involvement, to mild cases of limb girdle muscular dystrophies with late onset and no brain or eye involvement.

0960-8966/$ - see front matter Published by Elsevier B.V. http://dx.doi.org/10.1016/j.nmd.2012.05.006

Until recently a dystroglycanopathy phenotype has been found associated with mutations in six genes coding for putative and demonstrated glycosyltransferases or accessory proteins of glycosyltransferases : Protein-O-mannosyl transferase 1 (POMT1; OMIM 607423), Protein-O-manno-syl transferase 2 (POMT2; OMIM 607439), Protein-O-mannose 1,2-N-acetylglucosaminyltransferase 1 (POM-GnT1; OMIM 606822), fukutin (FKTN; OMIM 607440), Fukutin-related protein (FKRP; OMIM 606596) and LARGE (OMIM 603590) [2-7]. Recent suggestions that congenital muscular dystrophy (CMD) secondary to decreased a-dystroglycan expression may also be found associated with N-glycosylation disorders or mutations in dystroglycan itself are still limited to single cases [8].

Patients with dystroglycanopathies have common features, such as predominant involvement of the upper limbs and elevated CK but the spectrum of clinical severity ranges from the severe WWS, MEB and FCMD with severe structural muscle, eye and brain involvement, to milder cases with late onset and no brain or eye involvement.

Two studies on large cohorts have demonstrated that mutations in individual genes can be associated with different phenotypes and that, conversely, the same phenotype can be found in association with different known genes. [9,10]. Approximately half of the dystroglycanopathy patients do not have mutations in the known genes, this suggesting further genetic heterogeneity [9,10]. Patients with unknown mutations often have similar phenotypes to the cases in whom mutations have been identified, these findings strongly suggesting that the identity of the defective gene (or the absence of mutations in the known genes) cannot be predicted from the clinical phenotype.

All the previous studies reporting phenotypes in patients with known and unknown mutations have mainly focused on brain and eye involvement and maximal functional ability while little has been reported about other clinical aspects, such as severity of cardiac or respiratory involvement, which are common in other forms of congenital muscular dystrophy [11,12].

The aim of this retrospective study was to review respiratory and cardiac data in a large cohort of patients with CMD and reduction of alpha dystroglycan and their relationship with genetic and brain MRI findings.

2. Patients and methods

2.1. Patients

All patients had a diagnosis of CMD with a-DG deficiency. Inclusion criteria were early presentation (neonatal or delayed acquisition early milestones), myopathic/dystro-phic changes on muscle biopsy, and deficiency of a-DG on the sarcolemma of skeletal muscle fibers [13,14].

Because of the possible overlap with early onset limb girdle muscular dystrophies, it has recently been suggested that CMD should include cases with onset of weakness pre-natally or within the first months of life, before ambulation

is acquired. LGMD in contrast, would include the cases with onset after ambulation has been acquired.

All the patients included in this study had already been included in two previous large multicentric studies reporting muscle, eye and brain involvement and motor abilities. Details of the cohorts and of their genetic background, including methodology in genetic screening have already been reported [9,10]. We limited this study to those patients who had been seen at least once at one of the participating centers and in whom there was at least one assessment of cardiac and respiratory function.

2.2. Clinical data

Data were collected retrospectively using a structured proforma, noting information from overnight oximetry sleep studies and, when available, forced vital capacity (FVC) and cardiac function studies including electrocardi-ography (ECG) and echocardiogram results.

Echocardiogram was defined as abnormal if there were congenital abnormalities, signs of dilated cardiomyopathy or of decreased left ventricular systolic function.

3. Results

One hundred and fifteen patients fulfilled the inclusion criteria. Thirteen of the 115 died between 1 month and 20 years. The age at last follow up of the surviving 102 ranged between 1 year and 68 years (median: 9.3 years).

All data were analyzed subdividing the respiratory and cardiac function according to genetic findings and to the classification of phenotypes based on MRI and cognitive findings [9,10].

3.1. Cardiac function

Only 7 of the 115 had signs of cardiac involvement, 5 had dilated cardiomyopathy, one had mitral valve regurgitation and one mild conduction defects. There was no specific association between mutations or clinical phenotypes and cardiac function (Tables 1-3). On echocardiography another child was found to have aortic coartation but no ECG or echocardiogram abnormality.

3.2. Respiratory function

All patients had at least one measurement of overnight oxygen saturation. Fourteen of the 115 (12%) required ventilator support at the time of this study. Ten of these 14 patients had signs of nocturnal hypoventilation and were started on non invasive respiratory support, while the other four required tracheostomy due to acute respiratory distress. Table 1 shows details of the patients with respiratory impairment. There was no specific correlation between mutations or clinical phenotypes and respiratory function (Tables 2 and 3).

Table 1

Individual details of patients with abnormal cardiac or respiratory findings.

Patient Mutation Brain MRI Non invasive Tracheostomy/age Cardiac involvement Age at onset Age follow up Age at death

ventilation/age

1 FKRP Normal - - DCM 4 years - 6 years

2 FKRP MEB - - DCM 2 years 4 years -

3 FKRP Normal - - DCM 4 years 7 years -

4 POMT1 Normal - - DCM 19 years 20 years -

5 POMT2 MEB - - DCM -

6 Negative Atrophy - - Conductions defects 58 years 68 years -

7 Negative Normal - - Mitral regurgitation 12 years 14 years -

8 Negative Normal Neonatal - - - 5 years -

9 Negative MEB Neonatal - - - - 1 month

10 Negative Atrophy Neonatal - - - 10 years -

11 Negative Normal Neonatal - - - 9 years -

12 FKRP White matter 6 months - - - 8 years -

13 FKRP Normal 9 years - - - 10 years -

14 FKRP Normal 13 years - - - 14 years -

15 POMT2 Hydrocephalus 19 years - - - - 20 years

16 Negative White matter 20 years - - - 21 years

17 Negative Cerebellar - Neonatal - - 6 years

18 POMT2 Cerebellar - 3 years - - 13 years

19 Negative Cerebellar - 4 years - - - 6 years

20 Negative Cerebellar - - - - - 7 months

21 Negative Cerebellar - - - - - 16 months

22 Negative Cerebellar - - - - - 13 years

23 POMT2 Cerebellar - 7 years - - - 12 years

24 POMGnTl MEB neonatal

25 POMT1 WWS - - - - - 4 years

26 POMT2 WWS Neonatal

27 Negative WWS Neonatal

28 Negative WWS Neonatal

MEB, muscle eye brain disease; WWS, Walker Warburg syndrome; DCM, dilated cardiomyopathy.

Table 2

Genetic and clinical findings.

Abnormal cardiac function Respiratory failure Death

FKRP (n = 13) 3/13 (23%) 3/13 (23%) 1/13 (7.6%)

POMT1 (n = 14) 1/14 (7 %) 1/14 (7%) 1/14 (7%)

POMT2 (n = 10) 1/10 (1%) 3/10 (3%) 3/10 (3%)

POMGNT1 (n =18) 0/18 0/18 1/18 (5.5%)

LARGE (n = 2) 0/2 0/2 0/2

FKTN (n = 1) 0/1 0/1 0/1

All negative (n = 57) 2/57 (3.5%) 7/57 (12%) 7/57(12%)

Table 3

Brain MRI and clinical findings.

Abnormal cardiac function Respiratory failure Death

Normal brain MRI, no mental retardation (n = 8) 3/8 (37.5%) 2/8 (25%) 1/8 (12.5%)

Normal brain MRI, mental retardation (n = 26) 1/26 (3.8%) 3/26 (11.5%) 0/26

Cerebellar involvement (n = 20) 0/20 4/20 (20%) 5/20 (25%)

MEB (n = 35) 2/35 (5.7%) 1/35 (2.8%) 2/35 (5.7%)

WWS (n = 8) 0/8 0/8 4/8 (50%)

Hydrocephalus/Chiari (n = 7) 0/7 1/7 (14%) 1/7 (14%)

Brain atrophy (n = 5) 1/5 (20%) 1/5 (20%) 0/5

White matter (n = 6) 0/6 2/6 (33%) 0/6

FVC could not be reliably recorded in the majority of ondary to mental retardation, or macroglossia or the patients due to young age, lack of collaboration sec- malocclusion.

3.3. Survival

Thirteen patients died, four from intractable seizures and the other nine for severe acute events leading to respiratory failure (Tables 1-3). No postmortem was performed to ascertain causes of death.

4. Discussion

The aim of this retrospective study was to assess cardiac and respiratory function in a large cohort of patients with CMD and reduction of a-dystroglycan on muscle biopsy. Cardiac function was found to be impaired in only 7 of the 115 children. These patients carried mutations in FKRP, POMT1 and POMT2. One patient with LARGE mutations had an aortic coartation but no signs of primary cardiac involvement.

Cardiac abnormalities have already been reported in CMD patients with dystroglycanopathies [15-18], mainly associated with FKRP and fukutin mutations. In particular, dilated cardiomyopathy has been found to occur frequently in patients with FKRP mutations and LGMD2I phenotype [19-22] but has also been reported in five cases of patients with CMD phenotype [15,23-25]. In our cohort including only CMD patients, cardiac involvement was found in 3 of the 13 patients with FKRP mutations, two of whom had already been reported [15].

We also found dilated cardiomyopathy in a patient carrying POMT2 mutation and in one patient with POMT1 mutations. To our knowledge, with the exception of a report of left ventricular hypertrophy in a patient with POMT2 mutations [18], this is the first report of cardiac involvement in patients with CMD due to POMT1 and POMT2 mutations.

As we only had one patient with FKTN mutations and two with LARGE mutations we cannot draw any conclusion on possible cardiac involvement that has been previously reported to be frequent in patients with CMD and FKTN mutations in Japan [17].

Cardiac involvement appeared to occur infrequently in the groups without mutations in the known genes. Only one patient developed conduction defects at the age of 58 years.

Our findings confirm previous observations that cardiac impairment is relatively rare in this group of disorders. When found, cardiac abnormalities were already present before 12 years of age in 4 of the 7 cases. We believe that the low detection rate cannot be attributed to the age of the patients studied as more than 35% of our cohort was above the age of 12 and, in 5 cases, above the age of 20 years at the time of the study.

Impairment of respiratory function was also not common, occurring in only 14 of the 115 (12%) patients. Unfortunately, because of age, limited cooperation, mental retardation and in a number of cases, macroglossia or malocclusion, the majority of patients did not have reliable measurements of FVC and we cannot provide an estimate

of their values according to age. Sleep studies however were available in all patients studied, with 14 patients requiring ventilator support. Four of the 14 required invasive ventilation, inserted following an acute episode of respiratory distress. The other 10 had abnormal sleep studies which prompted the initiation of non invasive nocturnal ventilation. In 6 of the 10 ventilation was required before the age of one year.

Overall respiratory problems were also not frequent and not specifically associated with any of the known dystrogly-canopathy genes or individual phenotypes even though they were relatively more common in the patients with FKRP mutations, with normal brain MRI findings and no mental retardation, in those with POMT1 and POMT2 mutations with cerebellar involvement, microcephaly and mental retardation, and in a recently reported subgroup of CMD patients with severe intractable epilepsy [25]. The group with intractable epilepsy was also at higher risk of reduced survival as 4 of the 13 patients who died belonged to this subgroup.

In the large group of patients with POMGnTl mutations respiratory and cardiac impairment, never occurred even though one patient with MEB phenotype and POMGnTl mutations died in the first year for acute events.

Unlike other aspects of phenotype that are related to the severity of the mutations in the dystroglycanopathies, respiratory and cardiac function abnormalities were not specifically associated with the more severe MEB or WWS phenotypes, typically associated with mutations leading to severe functional defects (e.g., involvement of residues crucial for the enzymatic activity or those leading to frameshift and prematurely truncated protein) resulting in the severe brain, eye and muscle involvement. While these patients appear to be at higher risk of acute fatal events, those who survive early childhood do not demonstrate evidence of chronic progressive cardiac or respiratory impairment. In our cohort 4 of the 8 patients with WWS and 2 of the 35 with MEB died within the first years of life but none of the surviving patients with WWS pheno-type and only 2 of the 33 surviving MEB patients had cardiac abnormalities or progressive respiratory failure. These data are in agreement with previous limited studies also reporting that cardiac abnormalities are not frequent in WWS or MEB patients [12,26-28]. Since none of the patients who died in our series had autopsy studies, the causes of death were not always entirely clear and for this reason they were described separately. In two patients who died from acute cardiorespiratory complications, assessments performed months preceding death had been reported as normal this suggesting that death may occur due to severe acute cardiorespiratory events in fragile patients who often also have bulbar weakness.

One of the advantages of this study is that includes the largest cohort of CMD patients with dystroglycanopathy reported so far in the literature. The study was only possible because two large networks provided their retrospective data but this has limited the possibility to obtain more

detailed information on cardiac and respiratory function. Although the information collected are enough to exclude that severe signs of cardiac and respiratory impairment are common features in this cohort, prospective longitudinal studies are still needed to obtain more detailed information on the onset and the possible changes of cardiac and respiratory function over time. As many of the patients reported in this study were in the pediatric age, a longer follow up will also help to establish if some of them will develop cardiac and respiratory problems at a later age.

Acknowledgements

The Italian network is supported by a Telethon UILDM Grant (GUP 11001) and by a Ministry of Health Grant. The authors also thank the support of the National Commissioning Group to the Dubowitz Neuromuscular Centre for congenital muscular dystrophies and congenital myopathies. The support of the Muscular Dystrophy Campaign (MDC) to the Dubowitz Neuromuscular Centre is also gratefully acknowledged. ARF is a MDC clinical research fellow. FM is supported by Great Ormond Street Hospital Children's Charity.

References

[1] Muntoni F, Brockington M, Godfrey C, et al. Muscular dystrophies due to defective glycosylation of dystroglycan. Acta Myol 2007;26:129-35.

[2] Beltran-Valero de Bernabe D, Currier S, Steinbrecher A, et al. Mutations in the O-mannosyltransferase gene POMT1 give rise to the severe neuronal migration disorder Walker-Warburg syndrome. Am J Hum Genet 2002;71:1033-43.

[3] Brockington M, Blake DJ, Prandini P, et al. Mutations in the fukutin-related protein gene (FKRP) cause a form of congenital muscular dystrophy with secondary laminin alpha2 deficiency and abnormal glycosylation of alpha-dystroglycan. Am J Hum Genet 2001;69:1198-209.

[4] Kobayashi K, Nakahori Y, Miyake M, et al. An ancient retrotrans-posal insertion causes Fukuyama-type congenital muscular dystrophy. Nature 1998;394:388-92.

[5] Longman C, Brockington M, Torelli S, et al. Mutations in the human LARGE gene cause MDC1D, a novel form of congenital muscular dystrophy with severe mental retardation and abnormal glycosylation of alpha-dystroglycan. Hum Mol Genet 2003;12:2853-61.

[6] van Reeuwijk J, Janssen M, van den Elzen C, et al. POMT2 mutations cause alpha-dystroglycan hypoglycosylation and WalkerWarburg syndrome. J Med Genet 2005;42:907-12.

[7] Yoshida A, Kobayashi K, Manya H, et al. Muscular dystrophy and neuronal migration disorder caused by mutations in a glycosyltrans-ferase, POMGnT1. Dev Cell 2001;1:717-24.

[8] Lefeber DJ, Schonberger J, Morava E, et al. Deficiency of Dol-P-Man synthase subunit DPM3 bridges the congenital disorders of glycosylation with the dystroglycanopathies. Am J Hum Genet 2009;85:76-86.

[9] Godfrey C, Clement E, Mein R, et al. Refining genotype phenotype correlations in muscular dystrophies with defective glycosylation of dystroglycan. Brain 2007;130:2725-35.

[10] Mercuri E, Messina S, Bruno C, et al. Congenital muscular dystrophies with defective glycosylation ofdystroglycan: a population study. Neurology 2009;72:1802-9.

[11] Nadeau A, Kinali M, Main M, et al. Natural history of Ullrich congenital muscular dystrophy. Neurology 2009;73:25-31.

[12] Finsterer J, Ramaciotti C, Wang CH, et al. Cardiac findings in congenital muscular dystrophies. Pediatrics 2010;126:538-45.

[13] Brown SC, Torelli S, Brockington M, et al. Abnormalities in alpha-dystroglycan expression in MDC1C and LGMD2I muscular dystrophies. Am J Pathol 2004;164:727-37.

[14] Dubowitz V, Sewry CA. Muscle biopsy - a practical approach. Saunders; 2007.

[15] Mercuri E, Brockington M, Straub V, et al. Phenotypic spectrum associated with mutations in the fukutin-related protein gene. Ann Neurol 2003;53:537-42.

[16] Murakami T, Hayashi YK, Noguchi S, et al. Fukutin gene mutations cause dilated cardiomyopathy with minimal muscle weakness. Ann Neurol 2006;60:597-602.

[17] Nakanishi T, Sakauchi M, Kaneda Y, et al. Cardiac involvement in Fukuyama-type congenital muscular dystrophy. Pediatrics 2006;117:1187-92.

[18] Yanagisawa A, Bouchet C, Van den Bergh PY, et al. New POMT2 mutations causing congenital muscular dystrophy: identification of a founder mutation. Neurology 2007;69:1254-60.

[19] Poppe M, Bourke J, Eagle M, et al. Cardiac and respiratory failure in limb-girdle muscular dystrophy 2I. Ann Neurol 2004;56:738-41.

[20] Margeta M, Connolly AM, Winder TL, et al. Cardiac pathology exceeds skeletal muscle pathology in two cases of limb-girdle muscular dystrophy type 2I. Muscle Nerve 2009;40:883-9.

[21] Gaul C, Deschauer M, Tempelmann C, et al. Cardiac involvement in limb-girdle muscular dystrophy 2I: conventional cardiac diagnostic and cardiovascular magnetic resonance. J Neurol 2006;253:1317-22.

[22] Kefi M, Amouri R, Chabrak S, Mechmeche R, Hentati F. Variable cardiac involvement in Tunisian siblings harboring FKRP gene mutations. Neuropediatrics 2008;39:113-5.

[23] Louhichi N, Triki C, Quijano-Roy S, et al. New FKRP mutations causing congenital muscular dystrophy associated with mental retardation and central nervous system abnormalities. Identification of a founder mutation in Tunisian families. Neurogenetics 2004;5:27-34.

[24] MacLeod H, Pytel P, Wollmann R, et al. A novel FKRP mutation in congenital muscular dystrophy disrupts the dystrophin glycoprotein complex. Neuromuscul Disord 2007;17:285-9.

[25] Messina S, Tortorella G, Concolino D, et al. Congenital muscular dystrophy with defective alpha-dystroglycan, cerebellar hypoplasia, and epilepsy. Neurology 2009;73:1599-601.

[26] Kanoff RJ, Curless RG, Petito C, et al. Walker-Warburg syndrome: neurologic features and muscle membrane structure. Pediatr Neurol 1998;18:76-80, Review.

[27] Santavuori P, Valanne L, Autti T, et al. Muscle-eye-brain disease: clinical features, visual evoked potentials and brain imaging in 20 patients. Eur J Paediatr Neurol 1998;2:41-7.

[28] Hehr U, Uyanik G, Gross C, et al. Novel POMGnT1 mutations define broader phenotypic spectrum of muscle-eye-brain disease. Neurogenetics 2007;8:279-88.