Download genetic diagnostic criteria - Great Ormond Street Hospital

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Ext 0632/5849
National Specialist Commissioning Team
Rare Neuromuscular Disorders Diagnostic and Advisory
Service for congenital muscular dystrophies and congenital
myopathies
Dubowitz Neuromuscular Centre
Great Ormond Street Hospital for Children
Institute of Child Health
University College London
DNA Laboratory
Guy’s Hospital
Congenital Muscular Dystrophies and
Congenital Myopathies
Referral Criteria for DNA analysis
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Summary of Contents:
1.
Introduction .............................................................................................3
2.
Referral Criteria - Congenital Dystrophies ..............................................3
2.1
2.2
2.3
LAMA2 mutation screening.....................................................................3
SEPN1 mutation screening.....................................................................4
Secondary dystroglycanopathy genes (FKRP, POMT1, POMT2, POMGnT1,
Fukutin, LARGE) mutation screening .....................................................4
Ullrich CMD (COLL6) referrals
5
Bethlem myopathy (COLL6) referrals
................................5
CHKB mutation screening
....................................................6
Referral Criteria - Congenital Myopathies
RYR1 mutation screening .......................................................................6
MTM1 mutation screening .......................................................................8
DNM2 mutation screening .......................................................................8
BIN1 mutation screening .........................................................................9
ACTA1 mutation screening .....................................................................9
TPM2 .......................................................................................................9
TPM3 .....................................................................................................10
CFL2 ................................................................................................. 10
NEB exon 55 deletion mutation screen + linkage
10
2.4
2.5
2.6
3.
3.1
3.2
3.3
3.4
3.5
3.6
3.7
3.8
3.9
3
1.
Introduction
In order to target the molecular genetic screening service for the congenital muscular
dystrophies and myopathies to those patients in whom testing is most appropriate,
clinical referral criteria have been devised (as shown below). This will also help to
maximise the benefit of the service, within the activity level set by the service level
agreement that we have with the National Specialist Commissioning Team (Formerly
National Specialist Commissioning Group) who fund the service. The referral form and
clinicians contact details, for any patients referred for molecular testing that do not meet
this criteria, should be sent to dr Stephanie Robb at the Dubowitz Neuromuscular
Centre, Great Ormond Street Hospital so they can follow it up and offer advice to both
the referring clinician and to DNA lab at Guy’s as to what the most appropriate tests to
be carried out should be.
2.
Referral Criteria – Congenital Muscular Dystrophies
2.1
LAMA2 mutation screening
Absolute Indications
Positive family history
Absent/decreased LAMA2 on muscle biopsy
CMD phenotype with white matter changes in brain MRI
Minimum
Requirements
Congenital onset weakness with contractures plus;
Elevated CKs plus
If muscle biopsy but LAMA2 not done, offer to do it
under NSCT before proceeding
If no muscle biopsy, presence of white matter changes
on brain MRI in absence of cortical dysplasia
If no muscle biopsy or MRI, suggest discuss case with
clinicians
Contraindications –
review diagnosis
No contractures
Normal brain MRI above the age of 1 year
Independent walking achieved < 2 years *
Normal CKs < 5 years
*Only exceptionally achieved < 2y in partial merosin
deficiency
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2.2
SEPN1 mutation screening
Absolute Indications
Minimum
Requirements
Contraindications –
review diagnosis
2.3
Positive family history
Minicores or congenital fibre type disproportion on muscle
biopsy
CMD phenotype with marked spinal stiffness
Muscle MRI changes consistent with SEPN1 myopathy
Early onset hypotonia, weakness (axial> prox> distal) inc face
(mild)
Normal / mildly elevated CK
Motor delay, walking > 18months
Respiratory failure <20year or impairment with FVC<80%
Early spine rigidity
Early, progressive scoliosis
Cardiac involvement
CK > 6x normal
Structural brain involvement
Ophthalmoplegia is exceptional
Secondary dystroglycanopathy genes (FKRP, POMT1, POMT2, POMGnT1,
Fukutin, LARGE) mutation screening
Absolute Indications
Positive family history
CMD phenotype, elevated CK, reduced -dystroglycan
on muscle biopsy
Minimum
Requirements
CMD phenotype with structural changes on brain MRI
Offer to do -dystroglycan staining if frozen muscle
available
Contraindications –
review diagnosis
Normal CK < 5 years (normal CK may occur in
exceptional cases)
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2.4
Ullrich CMD referrals
Absolute Indications
Positive family history
Reduced/absent collagen VI in muscle, abnormal COL6
in fibroblast culture
CMD phenotype with typical concentric signal
abnormality on muscle MRI
Additional features
(screening can be
considered following
consultation with
Dubowitz clinicians)
Muscle biopsy showing dystrophic changes, offer to do
collagen VI under NCG service if muscle available
Congenital / early onset hypotonia, weakness
Distal laxity, proximal contractures
Normal / mildly elevated CK
Motor delay, walking > 18 months, loss of ambulation
<20 years
Progressive contractures
Keloid scarring/ Keratosis Pilaris
Cardiac involvement
CK > 2000
Structural brain involvement
Contraindications –
review diagnosis
2.5
Bethlem Myopathy Referrals
Absolute Indications
Additional Features
(screening can be
considered following
consultation with
Dubowitz clinicians)
Positive family history
Reduced/absent collagen VI in muscle, abnormal COL6
in fibroblast culture (in severe cases)
Contractural phenotype with typical concentric signal
abnormality on muscle MRI
Muscle biopsy mild, non specific changes, with only mild
increase in CT or fat. Offer to do Col6 staining
Congenital / early onset hypotonia, mild proximal
weakness and early distal laxity, progressing to
contractural phenotype (esp long finger flexors) with
mild proximal weakness +/- spinal stiffness
Keloid scarring/ Keratosis Pilaris
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Contraindications –
review diagnosis
2.6
elevated CK
Cardiac or brain involvement
Facial weakness, ptosis, ophthalmoplegia
CHKB CMD referrals
Absolute Indications
Positive family history of CHKB mutations
Learning difficulties +/- autism with no structural brain
abnormality with elevated CK and giant mitochondria on
muscle pathology
Additional features
(screening can be
considered following
consultation with
Dubowitz clinicians)
Icthyosis
Subtle deficiency of α dystroglycan and laminin α 2 on
muscle biopsy
Respiratory chain enzyme abnormalities
Contraindications –
review diagnosis
Normal CK
Severe structural brain involvement
3. Referral Criteria – Congenital Myopathies
3.1 RYR1 mutation screening
Absolute Indications Positive family history of MHS or RYR1 mutation
Fibre type uniformity and cores/minicores/central nuclei on
muscle biopsy, CFTD
MRI muscle with typical RYR1 selective involvement
Rhabdomyolysis with dominant family history
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Additional Features
(screening can be
considered following
consultation with
Dubowitz clinicians)
Congenital onset hypotonia and weakness with contractures
+/- congenital dislocation of hips
CK < 5 - 6 x normal
Weakness non/slowly progressive, legs > arms
+/- Scoliosis
Marked type 1 predominance on muscle biopsy, unevenness of
oxidative enzymes, CFTD, or centro-nuclear myopathy
Myofibrillar disruption on EM
SEPN1 gene excluded in patients with minicores
Contraindications –
review diagnosis
Cardiomyopathy
Structural brain involvement
CK > 1200
NB RYR1 testing for conditions not covered under the NSCT criteria (such as
recurrent rhabdomyolysis, statin – induced rhabdomyolysis) is available from the
GSTS DNA laboratory, but cannot be funded by the NSCT service. Alternative
funding arrangements should be agreed with the laboratory in advance.
3.2 MTM1
Absolute Indications
Positive family history of MTM1 mutation
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Muscle biopsy finding of centronuclear myopathy, highly
suggestive of MTM1 in a male (consider also in females,
especially if ‘necklace fibres’) with exclusion of myotonic
dystrophy
Additional Features
(screening can be
considered following
consultation with
Dubowitz clinicians)
Contraindications –
review diagnosis
3.3 DNM2
Absolute Indications
Additional Features
(screening can be
considered following
consultation with
Dubowitz clinicians)
Contraindications –
review diagnosis
Male neonate with severe congenital weakness,
respiratory impairment, facial and bulbar weakness and
ophthalmoplegia
+/- macrosomia and undescended testes
Milder, congenital myopathy in male (or rarely female)
with multiple central nuclei on muscle biopsy
Weak neonate with X-linked pattern of neonatal/infantile
deaths
elevated CK
Cardiac involvement
Positive family history of DNM2 mutation
Muscle biopsy finding of centronuclear myopathy,
especially with ‘radial strands’ , or with dominant family
history of myopathy
Centronuclear myopathy with muscle MRI changes
consistent with DNM2
Centronuclear myopathy with no mutations in MTM1
elevated CK
Cardiac involvement
NB We are unable to accept peripheral neuropathy referrals for DNM2 testing
under the NSCT service, but are able to consider the analysis at a charge.
3.4 BIN1
Absolute Indications
Positive family history of BIN1 mutations
Muscle biopsy finding of centronuclear myopathy, with
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family history of recessively inherited myopathy
Muscle MRI with changes consistent with BIN1
Additional Features
(screening can be
considered following
consultation with
Dubowitz clinicians)
Contraindications –
review diagnosis
3.5 ACTA1
Absolute Indications
Additional Features
(screening can be
considered following
consultation with
Dubowitz clinicians)
Contraindications –
review diagnosis
3.6 TPM2
Absolute Indications
Additional Features
(screening can be
considered following
consultation with
Dubowitz clinicians)
Contraindications –
review diagnosis
3.7 TPM3
Centronuclear myopathy with no mutations in MTM1 or
DNM2
elevated CK
Positive family history of ACTA1 mutations
Muscle biopsy finding of nemaline myopathy, especially
severe congenital onset
Congenital fibre type disproportion on muscle biopsy
Severe congenital myopathy in neonate with
contractures, but inconclusive muscle biopsy
elevated CK
Positive family history of TPM2 mutation
Muscle biopsy finding of nemaline myopathy or
congenital fibre type disproportion
Dominant distal arthrogryposis, muscle biopsy relatively
normal
elevated CK
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Absolute Indications
Additional Features
(screening can be
considered following
consultation with
Dubowitz clinicians)
Contraindications –
review diagnosis
3.8 CFL2
Absolute Indications
Additional Features
Screening can be
considered following
consultation with
Dubowitz clinicians)
Contraindications –
review diagnosis
Positive family history of TPM3 mutation
Muscle biopsy finding of nemaline myopathy
Congenital fibre type disproportion on muscle biopsy
elevated CK
Positive family history of CFL2 mutation
Muscle biopsy finding of nemaline myopathy with
negative mutations in ACTA1, TPM2&3 and NEB exon
55
Congenital fibre type disproportion on muscle biopsy
elevated CK
3.9 NEB exon 55 deletion screen + linkage
Absolute Indications Positive family history
Muscle biopsy finding of nemaline myopathy, especially
in a family of Ashkenazy Jewish descent
Muscle biopsy finding of nemaline myopathy with
negative mutations in ACTA1, TPM2&3 and CFL2
Additional Features
Screening can be
considered following
consultation with
Dubowitz clinicians)
Contraindications –
elevated CK
review diagnosis