Dr. Terencia/ Dr. Sajith Kesavan, Dr. GreeshmaIssac/ Dr. C Jayakumar
AIMS, Kochi
Six year old known case of RYR 1 heterozygous mutation (autosomal recessive congenital myopathy) presented with high grade intermittent fever and productive cough generalised body pain and lethargy of two days duration to an outside hospital. Heated humidified high flow nasal cannula ( HHHFNC) was stated due to the respiratory distress
in addition to antibiotics and other supportive measures.
As Child had persistent Respiratory distress with effortful breathing andworsening of sensorium, blood gas done showed type 2 respiratory failure and child required mechanical ventilation. At this time she was referred to AIMS
Perinatal history:
1st born of an NCM
H/o PIH at 8 months of gestation and decreased fetalmovements +.
Term, 2.6kgs birth weight, LSCS in view of Breech presentation and cord around neck. Child had a weak cry with respiratory distress for which she was shifted to NICU for 2 weeks and was treated for RDS.
In view of persistent weak cry and poor activities in neonatal period MRI brain was done at 1 month and was normal. Later all motor milestones were noted to be delayed and child was noted to be floppy with preserved Cognition.
On evaluation in an outside hospital CPK: 40IU and Clinical exome- a hetero VUS in RYR 1 gene in intron 91 c.13437+1G>A(5 ‘ splice site ) AD central core disease
Whole mitochondrial sequencing-Negative
H/o 2 episodes of pneumonia requiring hospital admissionswith prolonged stay in the past.
At 5 years of age Child was brought to AIMS for further evaluation and management. On evaluation child was noted to have Myopathic facies, Ptosis (B/l EOM palsy), Generalised muscle atrophy, Hyperextensible joints, Pectus excavatum, Lumbar lordosis and High pitch sound.
USG abdomen, MRI Brain and ECHO done was normal.
SMA screening was negative.
Genetics: RYR 1 heterozygous mutation (autosomal recessive congenital myopathy). Parents were evaluated and were found to be hetero-carriers
Nerve conduction studies Decreased/absent compound muscle action potential from right peronial, B/L ulnar and orbicularis oculi.
Child is under regular follow up in Pediatric neurology, genetics and Pediatric pulmonology.
Developmental History: She started walking at 2 years of age. Current- walks, climbs stairs with support. Immunised for age.
DIFFERENTIAL DIAGNOSIS:-
1.Sepsis
2. Lung collapse/consolidation
3.Pleural effusion
4.Empyema
At Admission
Child was on mechanical ventilation
Vitals HR: 150 bpm RR: PCV Mode Fio2 40% Pinsp 12 Peep 6 rate 25cpm BP: 100/70mm Hg Spo2: 98% on PCV mode
Myopathic facies, Ptosis B/l EOM palsy, Gen muscle atrophy,Hyperextensible joints, Pectus excavatum, Lumbar lordosiss,High pitch sound, Linear epidermal verrucae.
S/E-
RS: B/L air entry equal with S/c Emphysema over B/L neck region.
CVS: S1 S2 heard
PA: Soft
CNS: Proximal muscle weakness, hypotonia +
Child was shifted to PICU on ventilator from outside hospital with above mentioned complaints. Initial labs showed elevated counts(TC-25.75 ( K/uL )), N-86%, L-7%, HB-12.3g/dl, Plt-314 ( K/uL)
Figure 1- showing Admission chest x-ray with Subcutaneous emphysema, pneumomediastinum and pneumopericardium.
ET tube was changed to nasal. Once the air leak improved child was initiated on chest physiotherapy and cough assist. Respiratory viral panel sent was positive for Rhino/ Enterovirus. The child required invasive ventilation till day 7 of admission after which child was extubated into BiPaP and was continued on rigorous chest physiotherapy and cough assist. Child had a waxing and waning course of respiratory distress, requiring intensive chest physiotherapy with persistent left lower lobe collapse.
Figure 2 showing left lower lobe collapse
Genetic review and Pediatric neurology review was sought and counseled regarding the prognosis of the child and requirement of BiPAP support. The child was shifted to wardonce adequately tolerating off bipap breaks. As the child tolerated the off bipap breaks well, with twice daily LVR sessions. Parents were counselled regarding the need of chest physio and LVR and to use Bipap at home as advised. After parents were confident regarding the same child was being discharged with following advice.
CENTRAL CORE DISEASE
Central core disease (also called central core disease of muscle) was the first specific congenital mуοpаthy to be recognized.
Genetics — Most cases of central core disease are caused pathogenic variants in the gene encoding the ryanodine receptor (RΥR1) that is localized on chromosome 19q13.1 [28-32]. The gene product forms the key channel that mediates calcium release in skeletal muscle during excitation-contraction coupling. In at least one mutation in this gene, muscle ԝеаkոess in central core disease has been attributed to an uncoupling of excitation from calcium release.
Pathogenic variants in the RΥR1 gene also account for more than 50 percent of cases of malignant hyperthermia susceptibility
Pathogenic variants in RΥR1 have also been implicated as a cause of several other types of congenital mуораthieѕ, including multiminicore disease, centronuclear mуοраthу, and congenital fiber type disproportion.
Clinical features — Central core disease typically presents in the neonatal period, although it may sometimes not be recognized until later infancy. The principal clinical findings are hурοtоnia and muscle ԝеаkոeѕs, which usually are more prominent in the proximal extremities. Muscle involvement is variable and ranges from undetectable to severe.
Patients often have mild facial ԝеakոеѕѕ, but do not have ptosis, extraocular muscle ԝеаkոesѕ, dysphagia, or respiratory difficulty. Tendon reflexes usually are present, although they are reduced proportionally to the severity of the disease.
Musculoskeletal abnormalities commonly occur. They include congenital hip dislocation, kурhοѕϲοliοѕis, joint contractures, and foot deformities [34]. Affected patients are at risk for developing malignant hyperthermia.
The clinical course typically is nonprogressive. However, later progression of ԝеаkոesѕ can occur. Motor milestones usually are delayed.The creatine kinase level usually is normal. Еlеϲtrοmуоgraphy may show minor myopathic changes.
Diagnosis — The diagnosis is typically made genetic testing using a next generation sequencing targeted gene panel, whole exome sequencing, or whole genome sequencing. A muscle biopsy may still be valuable, particularly if variants of uncertain significance are identified.
Pathologic features — The diagnostic finding is the presence of cores of degenerated myofibrils in 20 to 100 percent of muscle fibers, which are predominantly type 1. The cores are central or slightly eccentric in location and may be single or multiple in a specific fiber. Histochemical stains for oxidative enzymes show lack of staining in the core region resulting from the absence of mitochondria. Atrophy of type 1 fibers is common.
TAKE OVER MESSAGE:-
Central core disease (CCD) is a rare genetic neuromuscular disorder that is classified as a congenital myopathy, meaning that it is present at birth (congenital) and is a disorder that causes muscle weakness (myopathy). Even trivial infections in these patients can result in mortality and severe morbidity in children with congenital myopathy -central core disease variant. Hence It’s essential to anticipate and initiate effective treatment with adequate respiratory support as early as possible.