Accepted Manuscript Case report Early infantile sensory-motor neuropathy with late onset respiratory distress Astrid Blaschek, Dieter Gläser, Marius Kuhn, Andreas Sebastian Schroeder, Cornelius Wimmer, Bernd Heimkes, Carola Schön, Wolfgang Müller-Felber PII: DOI: Reference:
S0960-8966(13)01019-5 http://dx.doi.org/10.1016/j.nmd.2013.11.013 NMD 2817
To appear in:
Neuromuscular Disorders
Received Date: Revised Date: Accepted Date:
4 June 2013 25 October 2013 22 November 2013
Please cite this article as: Blaschek, A., Gläser, D., Kuhn, M., Schroeder, A.S., Wimmer, C., Heimkes, B., Schön, C., Müller-Felber, W., Early infantile sensory-motor neuropathy with late onset respiratory distress, Neuromuscular Disorders (2013), doi: http://dx.doi.org/10.1016/j.nmd.2013.11.013
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Juvenile SMARD 1
1
Title:
2
Early infantile sensory-motor neuropathy with late onset respiratory distress
3
Astrid Blaschek1, Dieter Gläser2, Marius Kuhn2, Andreas Sebastian Schroeder1,3
4
Cornelius Wimmer4, Bernd Heimkes5, Carola Schön6, Wolfgang Müller-Felber1
5
1
6
Children´s Hospital, Ludwig-Maximilians-University Munich, Germany
7
2
Genetikum, Neu-Ulm, Germany
8
3
German Center for Vertigo and Balance Disorders, Munich University Hospital,
9
Germany
10
Department of Paediatric Neurology and Developmental Medicine, Dr. von Hauner
4
Schön Klinik Vogtareuth, Spinal Surgery with Scoliosis Centre, Vogtareuth,
11
Germany
12
5
13
Munich, Campus Grosshadern, Ludwig-Maximilians-University Munich, Germany
14
6
15
Germany
16
Corresponding author:
17
Astrid Blaschek MD
18
Department of Paediatric Neurology and Developmental Medicine
19
Dr. von Hauner Children´s Hospital, Ludwig-Maximilians-University Munich
20
Lindwurmstrasse 4, 80337 Munich, Germany
21
Phone: +49-89-5160-7851; Fax: +49-89-5160-7745
22
Email: [email protected]
Department of Orthopedic Surgery, Pediatric Orthopedic Unit, University Hospital
Dr. von Hauner Children´s Hospital, Ludwig-Maximilians-University Munich,
1
Juvenile SMARD 2 1 2
Abstract:
3
Children with spinal muscular atrophy with respiratory distress (SMARD1) usually
4
present within their first year of life with respiratory failure due to diaphragmatic
5
paralysis and progressive distal limb weakness. We present a child with a confirmed
6
compound heterozygous IGHMBP2 mutation c.[676G>T];[2083A>T] in whom severe
7
sensory-motor neuropathy preceded diaphragmatic paralysis by almost 3 years.
8
Autonomic system involvement with neurogenic bladder and urine retention were
9
found at 3 years. In summary our patient highlights the broad spectrum of
10
phenotypes observed in SMARD1. Currently no prediction of phenotype according to
11
genotype is possible suggesting that yet unknown factors cause the observed
12
phenotypic variation. Even in the absence of obvious diaphragmatic weakness
13
SMARD1 should be considered in severe infantile onset neuropathies. High
14
throughput techniques such as next generation sequencing will possibly offer a
15
useful approach in the heterogeneous group of inherited neuropathies.
16 17
Word count abstract: 137 words
18
Keywords:
2
Juvenile SMARD 3 1
SMARD 1
2
Respiratory distress
3
Distal neuropathy
4
IGHMBP2
5
Autonomic neuropathy
3
Juvenile SMARD 4 1
Introduction
2
Patients with spinal muscular atrophy with respiratory distress (SMARD1) typically
3
present with low birth weight, progressive distal limb weakness and diaphragmatic
4
paralysis resulting in severe respiratory failure within the first year of life [1, 2]. The
5
most prominent presenting symptom is a rapidly progressive, severe respiratory
6
distress which often results in an emergency intubation and subsequent need of
7
artificial ventilation.
8
In 2001 the underlying mutation in the IGHMBP2 gene was identified which encodes
9
the immunoglobulin µ-binding protein 2 on chromosome 11q13.3 [3]. Functional and
10
structural data show that the protein belongs to a helicase family involved in ATP-
11
dependant mRNA decay [4, 5]. Mutations in IGHMBP2 gene have been proposed to
12
impair mostly ATPase and helicase activity [4].
13
Apart from classic neonatal/ infantile presentation there have been only a few reports
14
of unusual late or mild cases [6-8]. We present a child with confirmed compound
15
heterozygous IGHMBP2 mutations in whom a severe sensory-motor polyneuropathy
16
with distal weakness in the arms, generalized weakness in the legs and dysphagia
17
preceded diaphragmatic paralysis by almost 3 years.
18
4
Juvenile SMARD 5 1
Case report
2
The girl is the first child of healthy non-consanguineous Caucasian parents. The
3
pregnancy was complicated by oligohydramnios and suspected placental
4
insufficiency. She was born by caesarian section at 35+6 weeks of gestation with
5
weight, length and head circumference below the 3rd percentile indicating
6
intrauterine growth retardation. In addition a right-sided pes calcaneus was noted
7
after birth together with cardiac abnormalities (patent foramen ovale and patent
8
ductus arteriosus). Postnatal adaption was unremarkable and the child was
9
discharged from the neonatal ward 2 weeks after birth. In the first months of life the
10
parents noticed reduced spontaneous movements of the legs. Neurologic
11
examination at 5 months showed severely reduced spontaneous movements mainly
12
in the legs, bilateral pes adductus and reduced deep tendon reflexes. At 10 months
13
paresis of the intrinsic hand muscles with the development of claw hands was found.
14
At that time no compound muscle action potential (CMAP) could be recorded from
15
the thenar muscles (median nerve), abductor digiti V (ulnar nerve), extensor
16
digitorum brevis muscle and anterior tibial muscle (peroneal nerve) and abductor
17
hallucis and gastrocnemius (tibeal nerve). Equally, sural and median sensory nerve
18
action potentials could not be elicited. Electromyography of the abductor pollicis
19
brevis and extensor digitorum brevis muscle revealed no pathological spontaneous
20
activity at rest and no MUAPs on voluntary innervation. In the quadriceps femoris
21
muscle there was no spontaneous activity at rest and a neurogenic pattern on
22
voluntary activation. The EMG of the biceps brachii muscle was completely normal.
23
At 1 year of age there was a severe distally pronounced weakness of the legs and
24
arms with absent deep tendon reflexes. The mother reported that the child had
25
difficulties with swallowing liquids and choked occasionally on pureed baby food. 5
Juvenile SMARD 6 1
Over the next months feeding became more time consuming and weight gain slowed
2
markedly down, which has been along the 3rd percentile up until 12 months. With a
3
home based pulse oximeter no signs of nocturnal desaturation were reported by
4
parents.
5
At 2 3/12 years first signs of scoliosis were noted during hospital admittance due to
6
aspiration associated pneumonia. A chest x-ray demonstrated bilateral signs of acute
7
pneumonia and a mild right-sided thoracic scoliosis, but no diaphragmatic paralysis
8
(figure 1a, 2 3/12 years). Within the next two months she had to be admitted twice
9
with respiratory problems related to aspiration associated pneumonia leading to night
10
time CPAP ventilation and tube feeding at 2 5/12 years. During that time her
11
neurologic function deteriorated in that she was no longer able to sit unsupported. In
12
the following 6 months her respiratory function, hand and arm function declined
13
notably. Urine retention required intermittent catheterization. There was a rapid
14
progression of scoliosis with the need of surgery and a worsening of respiration
15
during daytime. At the same time reduced diaphragmatic movements were found for
16
the first time (figure 1b, 3 2/12 years).
17
At 3 3/12 years tracheostomy was performed and four months later stabilization of
18
her vertebral spine was done without complications.
19
At the age of 3 years a next generation sequencing (NGS) panel for hereditary
20
neuropathies revealed two compound heterozygous mutations in the IGHMBP2 gene
21
c.[676G>T];[2083A>T] leading most probably to a truncated protein
22
p.[Glu226*];[Lys695*]. Her father is a heterozygous carrier for the c.676G>T
23
(p.Glu226X) mutation and her mother for the c2083A>T (p.Lys695X).
6
Juvenile SMARD 7 1
Discussion
2
SMARD1 is an autosomal-recessive disorder caused by mutations in the IGHMBP2.
3
Typical cases of SMARD1 present with early-onset respiratory failure due to
4
diaphragmatic weakness in the first year of life, requiring mechanical ventilation [1,
5
2]. Apart from classic neonatal/ infantile presentation there have been only a few
6
reports of unusual late or mild cases [6-8]. We present a child with a confirmed
7
compound heterozygous SMARD 1 mutation in whom a severe early onset sensory
8
motor neuropathy preceded diaphragmatic paralysis by almost 3 years. Diagnosis of
9
SMARD1 was made before diaphragmal eventration was visible on chest x-rays
10
based on identification of 2 mutations in the IGHMBP2 gene with NGS gene panel for
11
hereditary neuropathies.
12
Autonomic symptoms with urinary retention appeared as early as at 3 ½ years,
13
indicating that in some cases SMARD1 there is a mixed polyneuropathy which affects
14
small as well as large nerve fibers. Until now neurogenic bladder has been described
15
mostly in severe early onset cases and only in one juvenile case before with a late
16
onset at the age of 9 years [7, 9].
17
Findings in our patient highlight the phenotypic heterogeneity in SMARD1. The
18
Human IGHMBP2 contains 15 exons with an RNA/DNA helicase, an R3H (single-
19
stranded nucleic acid-binding) and a zinc finger domain. In neurons IGHMBP2 is
20
largely found in the cytosolic component, supporting proposed functions in RNA
21
processing, regulation or metabolism [4, 5]. The two mutations in our patient have not
22
been described, but both mutations result in premature stop codons. The c.676G>T
23
(p.Glu226X) mutation in exon 5 is located in the predicted helicase core of Human
24
IGHMBP2 and mutations herein are proposed to affect ATPase activity [5]. The
25
c.2083A>T (p.Lys695X) mutation in exon 13 is located in the ssDNA binding region. 7
Juvenile SMARD 8 1
To date no data allows the prediction of the phenotype according to genotype in
2
SMARD1. Joseph et al. described to two siblings with identical gene mutations and a
3
remarkable phenotypic variability, with one of them dying of respiratory failure at 6
4
months and the other still alive at 12 years with limb weakness and mild nocturnal
5
hypoventilation [8]. Thus modifying factors must be present to account for the
6
observed phenotypic variability. In nmd mouse, an animal model for SMARD,
7
evidence for modifying genetic factors that slow the progression of disease have
8
been published [10]. To our knowledge no data on humans are available. Different
9
modifiers might alter level of residual protein to explain clinical variability. This
10
hypothesis is supported by Guenther et al. who found elevated protein levels of
11
IGHMBP2 in the two patients with late onset disease when compared to classic
12
presentation [7]. Whether different protein levels resulted from characteristics of the
13
mutations in IGHMBP2 gene itself or from other compensatory mechanisms cannot
14
be answered to date.
15 16
In summary our patient highlights the broad spectrum of phenotypes observed in
17
SMARD1. Even in the absence of obvious diaphragmatic weakness the diagnosis
18
should be considered in the differential diagnosis of early onset hereditary
19
neuropathies. High throughput genetic technologies should be taken into
20
consideration in unclassified infantile neuropathies.
21 22 23 24
Acknowledgement
25
We thank the family of the child described for consenting the publication. 8
Juvenile SMARD 9 1
Literature
2 3
[1]
Guenther UP, Varon R, Schlicke M, et al. Clinical and mutational profile in
4
spinal muscular atrophy with respiratory distress (SMARD): defining
5
novel phenotypes through hierarchical cluster analysis. Human mutation
6
2007;28:808-15.
7
[2]
Kaindl AM, Guenther UP, Rudnik-Schoneborn S, et al. Spinal muscular
8
atrophy with respiratory distress type 1 (SMARD1). Journal of child
9
neurology 2008;23:199-204.
10
[3]
Grohmann K, Schuelke M, Diers A, et al. Mutations in the gene encoding
11
immunoglobulin mu-binding protein 2 cause spinal muscular atrophy
12
with respiratory distress type 1. Nature genetics 2001;29:75-7.
13
[4]
Guenther UP, Handoko L, Laggerbauer B, et al. IGHMBP2 is a ribosome-
14
associated helicase inactive in the neuromuscular disorder distal SMA
15
type 1 (DSMA1). Human molecular genetics 2009;18:1288-300.
16
[5]
Lim SC, Bowler MW, Lai TF, Song H. The Ighmbp2 helicase structure
17
reveals the molecular basis for disease-causing mutations in DMSA1.
18
Nucleic acids research 2012;40:11009-22.
19
[6]
Guenther UP, Schuelke M, Bertini E, et al. Genomic rearrangements at
20
the IGHMBP2 gene locus in two patients with SMARD1. Human genetics
21
2004;115:319-26.
22
[7]
Guenther UP, Handoko L, Varon R, et al. Clinical variability in distal
23
spinal muscular atrophy type 1 (DSMA1): determination of steady-state
24
IGHMBP2 protein levels in five patients with infantile and juvenile
25
disease. Journal of molecular medicine 2009;87:31-41. 9
Juvenile SMARD 10 1
[8]
Joseph S, Robb SA, Mohammed S, et al. Interfamilial phenotypic
2
heterogeneity in SMARD1. Neuromuscular disorders : NMD 2009;19:193-
3
5.
4
[9]
Grohmann K, Varon R, Stolz P, et al. Infantile spinal muscular atrophy
5
with respiratory distress type 1 (SMARD1). Annals of neurology
6
2003;54:719-24.
7
[10]
Cox GA, Mahaffey CL, Frankel WN. Identification of the mouse
8
neuromuscular degeneration gene and mapping of a second site
9
suppressor allele. Neuron 1998;21:1327-37.
10 11
10
Juvenile SMARD 11 1
Figure1
2 3
Chest x-ray investigations of our patient at ages: (a) 2 3/12 years,
4
(b) 3 2/12 years. The series demonstrates late onset diaphragmatic eventration (b)
5
after manifestation of weakness and scoliosis.
6
7
11
S0960-8966(13)01019-5 http://dx.doi.org/10.1016/j.nmd.2013.11.013 NMD 2817
To appear in:
Neuromuscular Disorders
Received Date: Revised Date: Accepted Date:
4 June 2013 25 October 2013 22 November 2013
Please cite this article as: Blaschek, A., Gläser, D., Kuhn, M., Schroeder, A.S., Wimmer, C., Heimkes, B., Schön, C., Müller-Felber, W., Early infantile sensory-motor neuropathy with late onset respiratory distress, Neuromuscular Disorders (2013), doi: http://dx.doi.org/10.1016/j.nmd.2013.11.013
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Juvenile SMARD 1
1
Title:
2
Early infantile sensory-motor neuropathy with late onset respiratory distress
3
Astrid Blaschek1, Dieter Gläser2, Marius Kuhn2, Andreas Sebastian Schroeder1,3
4
Cornelius Wimmer4, Bernd Heimkes5, Carola Schön6, Wolfgang Müller-Felber1
5
1
6
Children´s Hospital, Ludwig-Maximilians-University Munich, Germany
7
2
Genetikum, Neu-Ulm, Germany
8
3
German Center for Vertigo and Balance Disorders, Munich University Hospital,
9
Germany
10
Department of Paediatric Neurology and Developmental Medicine, Dr. von Hauner
4
Schön Klinik Vogtareuth, Spinal Surgery with Scoliosis Centre, Vogtareuth,
11
Germany
12
5
13
Munich, Campus Grosshadern, Ludwig-Maximilians-University Munich, Germany
14
6
15
Germany
16
Corresponding author:
17
Astrid Blaschek MD
18
Department of Paediatric Neurology and Developmental Medicine
19
Dr. von Hauner Children´s Hospital, Ludwig-Maximilians-University Munich
20
Lindwurmstrasse 4, 80337 Munich, Germany
21
Phone: +49-89-5160-7851; Fax: +49-89-5160-7745
22
Email: [email protected]
Department of Orthopedic Surgery, Pediatric Orthopedic Unit, University Hospital
Dr. von Hauner Children´s Hospital, Ludwig-Maximilians-University Munich,
1
Juvenile SMARD 2 1 2
Abstract:
3
Children with spinal muscular atrophy with respiratory distress (SMARD1) usually
4
present within their first year of life with respiratory failure due to diaphragmatic
5
paralysis and progressive distal limb weakness. We present a child with a confirmed
6
compound heterozygous IGHMBP2 mutation c.[676G>T];[2083A>T] in whom severe
7
sensory-motor neuropathy preceded diaphragmatic paralysis by almost 3 years.
8
Autonomic system involvement with neurogenic bladder and urine retention were
9
found at 3 years. In summary our patient highlights the broad spectrum of
10
phenotypes observed in SMARD1. Currently no prediction of phenotype according to
11
genotype is possible suggesting that yet unknown factors cause the observed
12
phenotypic variation. Even in the absence of obvious diaphragmatic weakness
13
SMARD1 should be considered in severe infantile onset neuropathies. High
14
throughput techniques such as next generation sequencing will possibly offer a
15
useful approach in the heterogeneous group of inherited neuropathies.
16 17
Word count abstract: 137 words
18
Keywords:
2
Juvenile SMARD 3 1
SMARD 1
2
Respiratory distress
3
Distal neuropathy
4
IGHMBP2
5
Autonomic neuropathy
3
Juvenile SMARD 4 1
Introduction
2
Patients with spinal muscular atrophy with respiratory distress (SMARD1) typically
3
present with low birth weight, progressive distal limb weakness and diaphragmatic
4
paralysis resulting in severe respiratory failure within the first year of life [1, 2]. The
5
most prominent presenting symptom is a rapidly progressive, severe respiratory
6
distress which often results in an emergency intubation and subsequent need of
7
artificial ventilation.
8
In 2001 the underlying mutation in the IGHMBP2 gene was identified which encodes
9
the immunoglobulin µ-binding protein 2 on chromosome 11q13.3 [3]. Functional and
10
structural data show that the protein belongs to a helicase family involved in ATP-
11
dependant mRNA decay [4, 5]. Mutations in IGHMBP2 gene have been proposed to
12
impair mostly ATPase and helicase activity [4].
13
Apart from classic neonatal/ infantile presentation there have been only a few reports
14
of unusual late or mild cases [6-8]. We present a child with confirmed compound
15
heterozygous IGHMBP2 mutations in whom a severe sensory-motor polyneuropathy
16
with distal weakness in the arms, generalized weakness in the legs and dysphagia
17
preceded diaphragmatic paralysis by almost 3 years.
18
4
Juvenile SMARD 5 1
Case report
2
The girl is the first child of healthy non-consanguineous Caucasian parents. The
3
pregnancy was complicated by oligohydramnios and suspected placental
4
insufficiency. She was born by caesarian section at 35+6 weeks of gestation with
5
weight, length and head circumference below the 3rd percentile indicating
6
intrauterine growth retardation. In addition a right-sided pes calcaneus was noted
7
after birth together with cardiac abnormalities (patent foramen ovale and patent
8
ductus arteriosus). Postnatal adaption was unremarkable and the child was
9
discharged from the neonatal ward 2 weeks after birth. In the first months of life the
10
parents noticed reduced spontaneous movements of the legs. Neurologic
11
examination at 5 months showed severely reduced spontaneous movements mainly
12
in the legs, bilateral pes adductus and reduced deep tendon reflexes. At 10 months
13
paresis of the intrinsic hand muscles with the development of claw hands was found.
14
At that time no compound muscle action potential (CMAP) could be recorded from
15
the thenar muscles (median nerve), abductor digiti V (ulnar nerve), extensor
16
digitorum brevis muscle and anterior tibial muscle (peroneal nerve) and abductor
17
hallucis and gastrocnemius (tibeal nerve). Equally, sural and median sensory nerve
18
action potentials could not be elicited. Electromyography of the abductor pollicis
19
brevis and extensor digitorum brevis muscle revealed no pathological spontaneous
20
activity at rest and no MUAPs on voluntary innervation. In the quadriceps femoris
21
muscle there was no spontaneous activity at rest and a neurogenic pattern on
22
voluntary activation. The EMG of the biceps brachii muscle was completely normal.
23
At 1 year of age there was a severe distally pronounced weakness of the legs and
24
arms with absent deep tendon reflexes. The mother reported that the child had
25
difficulties with swallowing liquids and choked occasionally on pureed baby food. 5
Juvenile SMARD 6 1
Over the next months feeding became more time consuming and weight gain slowed
2
markedly down, which has been along the 3rd percentile up until 12 months. With a
3
home based pulse oximeter no signs of nocturnal desaturation were reported by
4
parents.
5
At 2 3/12 years first signs of scoliosis were noted during hospital admittance due to
6
aspiration associated pneumonia. A chest x-ray demonstrated bilateral signs of acute
7
pneumonia and a mild right-sided thoracic scoliosis, but no diaphragmatic paralysis
8
(figure 1a, 2 3/12 years). Within the next two months she had to be admitted twice
9
with respiratory problems related to aspiration associated pneumonia leading to night
10
time CPAP ventilation and tube feeding at 2 5/12 years. During that time her
11
neurologic function deteriorated in that she was no longer able to sit unsupported. In
12
the following 6 months her respiratory function, hand and arm function declined
13
notably. Urine retention required intermittent catheterization. There was a rapid
14
progression of scoliosis with the need of surgery and a worsening of respiration
15
during daytime. At the same time reduced diaphragmatic movements were found for
16
the first time (figure 1b, 3 2/12 years).
17
At 3 3/12 years tracheostomy was performed and four months later stabilization of
18
her vertebral spine was done without complications.
19
At the age of 3 years a next generation sequencing (NGS) panel for hereditary
20
neuropathies revealed two compound heterozygous mutations in the IGHMBP2 gene
21
c.[676G>T];[2083A>T] leading most probably to a truncated protein
22
p.[Glu226*];[Lys695*]. Her father is a heterozygous carrier for the c.676G>T
23
(p.Glu226X) mutation and her mother for the c2083A>T (p.Lys695X).
6
Juvenile SMARD 7 1
Discussion
2
SMARD1 is an autosomal-recessive disorder caused by mutations in the IGHMBP2.
3
Typical cases of SMARD1 present with early-onset respiratory failure due to
4
diaphragmatic weakness in the first year of life, requiring mechanical ventilation [1,
5
2]. Apart from classic neonatal/ infantile presentation there have been only a few
6
reports of unusual late or mild cases [6-8]. We present a child with a confirmed
7
compound heterozygous SMARD 1 mutation in whom a severe early onset sensory
8
motor neuropathy preceded diaphragmatic paralysis by almost 3 years. Diagnosis of
9
SMARD1 was made before diaphragmal eventration was visible on chest x-rays
10
based on identification of 2 mutations in the IGHMBP2 gene with NGS gene panel for
11
hereditary neuropathies.
12
Autonomic symptoms with urinary retention appeared as early as at 3 ½ years,
13
indicating that in some cases SMARD1 there is a mixed polyneuropathy which affects
14
small as well as large nerve fibers. Until now neurogenic bladder has been described
15
mostly in severe early onset cases and only in one juvenile case before with a late
16
onset at the age of 9 years [7, 9].
17
Findings in our patient highlight the phenotypic heterogeneity in SMARD1. The
18
Human IGHMBP2 contains 15 exons with an RNA/DNA helicase, an R3H (single-
19
stranded nucleic acid-binding) and a zinc finger domain. In neurons IGHMBP2 is
20
largely found in the cytosolic component, supporting proposed functions in RNA
21
processing, regulation or metabolism [4, 5]. The two mutations in our patient have not
22
been described, but both mutations result in premature stop codons. The c.676G>T
23
(p.Glu226X) mutation in exon 5 is located in the predicted helicase core of Human
24
IGHMBP2 and mutations herein are proposed to affect ATPase activity [5]. The
25
c.2083A>T (p.Lys695X) mutation in exon 13 is located in the ssDNA binding region. 7
Juvenile SMARD 8 1
To date no data allows the prediction of the phenotype according to genotype in
2
SMARD1. Joseph et al. described to two siblings with identical gene mutations and a
3
remarkable phenotypic variability, with one of them dying of respiratory failure at 6
4
months and the other still alive at 12 years with limb weakness and mild nocturnal
5
hypoventilation [8]. Thus modifying factors must be present to account for the
6
observed phenotypic variability. In nmd mouse, an animal model for SMARD,
7
evidence for modifying genetic factors that slow the progression of disease have
8
been published [10]. To our knowledge no data on humans are available. Different
9
modifiers might alter level of residual protein to explain clinical variability. This
10
hypothesis is supported by Guenther et al. who found elevated protein levels of
11
IGHMBP2 in the two patients with late onset disease when compared to classic
12
presentation [7]. Whether different protein levels resulted from characteristics of the
13
mutations in IGHMBP2 gene itself or from other compensatory mechanisms cannot
14
be answered to date.
15 16
In summary our patient highlights the broad spectrum of phenotypes observed in
17
SMARD1. Even in the absence of obvious diaphragmatic weakness the diagnosis
18
should be considered in the differential diagnosis of early onset hereditary
19
neuropathies. High throughput genetic technologies should be taken into
20
consideration in unclassified infantile neuropathies.
21 22 23 24
Acknowledgement
25
We thank the family of the child described for consenting the publication. 8
Juvenile SMARD 9 1
Literature
2 3
[1]
Guenther UP, Varon R, Schlicke M, et al. Clinical and mutational profile in
4
spinal muscular atrophy with respiratory distress (SMARD): defining
5
novel phenotypes through hierarchical cluster analysis. Human mutation
6
2007;28:808-15.
7
[2]
Kaindl AM, Guenther UP, Rudnik-Schoneborn S, et al. Spinal muscular
8
atrophy with respiratory distress type 1 (SMARD1). Journal of child
9
neurology 2008;23:199-204.
10
[3]
Grohmann K, Schuelke M, Diers A, et al. Mutations in the gene encoding
11
immunoglobulin mu-binding protein 2 cause spinal muscular atrophy
12
with respiratory distress type 1. Nature genetics 2001;29:75-7.
13
[4]
Guenther UP, Handoko L, Laggerbauer B, et al. IGHMBP2 is a ribosome-
14
associated helicase inactive in the neuromuscular disorder distal SMA
15
type 1 (DSMA1). Human molecular genetics 2009;18:1288-300.
16
[5]
Lim SC, Bowler MW, Lai TF, Song H. The Ighmbp2 helicase structure
17
reveals the molecular basis for disease-causing mutations in DMSA1.
18
Nucleic acids research 2012;40:11009-22.
19
[6]
Guenther UP, Schuelke M, Bertini E, et al. Genomic rearrangements at
20
the IGHMBP2 gene locus in two patients with SMARD1. Human genetics
21
2004;115:319-26.
22
[7]
Guenther UP, Handoko L, Varon R, et al. Clinical variability in distal
23
spinal muscular atrophy type 1 (DSMA1): determination of steady-state
24
IGHMBP2 protein levels in five patients with infantile and juvenile
25
disease. Journal of molecular medicine 2009;87:31-41. 9
Juvenile SMARD 10 1
[8]
Joseph S, Robb SA, Mohammed S, et al. Interfamilial phenotypic
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heterogeneity in SMARD1. Neuromuscular disorders : NMD 2009;19:193-
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5.
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[9]
Grohmann K, Varon R, Stolz P, et al. Infantile spinal muscular atrophy
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with respiratory distress type 1 (SMARD1). Annals of neurology
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2003;54:719-24.
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[10]
Cox GA, Mahaffey CL, Frankel WN. Identification of the mouse
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neuromuscular degeneration gene and mapping of a second site
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suppressor allele. Neuron 1998;21:1327-37.
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Juvenile SMARD 11 1
Figure1
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Chest x-ray investigations of our patient at ages: (a) 2 3/12 years,
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(b) 3 2/12 years. The series demonstrates late onset diaphragmatic eventration (b)
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after manifestation of weakness and scoliosis.
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