Family 1

The whole exome sequencing performed on the child highlighted the presence of compound heterozygous TANGO2 mutations. The nature of the two heterozygous variants, nonsense p.Arg88*, inherited from mother, and p.Glu112fs frameshift, inherited from father, points to a virtually complete functional knock-out of the TANGO2 protein in the proband.

Before being diagnosed the Tango 2 mutation, the child had three severe episodes of rhabdomyolysis (at 13, 27 and 28 months old) with cognitive and motor impairment.

0 – 12 months
He was breastfed until 6th month without regurgitation, vomit and colics. Regular weaning. Occurrence of milk crust at about 7 months, potential intolerance to lactose (negative allergy tests at 18 months old). An ongoing lactose-free diet was introduced. He ate all foods with pleasure, notably pasta and meat, with no mastication/deglutition problems. He did not drink much. Since weaning, he refused to drink any continuation milk. Normal dentition: teeth are small and spaced out. Standard weight, growth and head circumference.
• Motor development: He showed a limited use of the inferior limbs. He acquired sitting posture at 8 months old. At 10 months old, he started moving around by crawling backwards with the use of his arms. At 11 months, he started quadrupedia but did not crawl. When put in upright position, he kept it by clutching at an object.
• Cognitive development: He was sociable, made attempts to establish eye contacts and interacted with those around him. He smiled and followed carefully all the events around him. He made no sounds, no lallation. He generally didn’t sleep much at night (about 8 hours) and waked up 2-3 times per night, depending on the period. Morning and afternoon sleep: about 1 hour and 2-3 hours, respectively.

1st episode of rhabdomyolysis (13 months old)
In the 3 days before the acute episode, he ate and drank very little, probably due to sore throat. No fever. He became more and more tired and narcoleptic. He was not able to keep an upright position and lost his balance. He was hospitalized at the hospital for acute rhabdomyolysis.
Within 72 hours after hospitalization, CK value had risen to 220,000 (ul/L); Administration of cortisone therapy and hydration. Following this peak, CK value rapidly decreased in the following days. The high transaminase levels recorded during the acute phase progressively decreased to normal values within a few weeks.
During this episode the following were observed:
• mild hypothyroidism diagnosed (start of hospitalization FT3 2,58, FT4 8,29);
• thyroid scintigraphy showed a small thyroid; start of the ongoing alternative therapy with L-thyroxine.
• Severe hyponatremia (NA 115) which led to a deep comatose state (GCS10) for 1 week;
• Cardiac complications: increase in the values of CK-MB (max. 146 ng/mL, normal value <5) and Troponin T (max. 1.14 ug/L, normal value <0.014), ECG altered, altered ripolarization, below-level in lower area, small over-level DI to VI, QTc long and reduction of heart ejection fraction (45-50%). Clinical situation within normal limits some weeks later. Between 1st and 2nd episode of rhabdomyolysis (15-26 months old).
Motor development: In the period between the first and the second hospitalization, he slowly regained muscle tone and started crawling at 18 months old. At 21 months old, he started holding himself upright by clutching at a frontal support. He gradually increased the length of his standings and, at 24 months old, he started moving laterally, always using a support. If held, he tried to move a few steps. No deambulation.
• Cognitive development: he started producing a few sounds, without real lallation. He understood simple orders: wave/clap your hands; pass/give me, etc. He produced sounds not clearly related to objects, pointed at and generated sounds if he wanted something in particular. He did not imitate adults and played in a repetitive way, without significant evolution in its complexity (e.g. knocking building blocks down, but without building them up again).

2nd episode of rhabdomyolysis (27 months old).
In the 3 days before the acute episode, he had fever (39°C) and ate and drank very little. He became more and more tired and plaintive. Within 48 hours CK value raised to that observed in the first episode ( 225,000). Forced intravenous hydration. Administration of sodium bicarbonate and paracetamol. No cortisone.
During this episode the following were observed:
• Lactate at the start of hospitalization: 4.5 (normal value <2.2). • Cardiac complications: weakened septum, high values of CK-MB and Troponin T. • The EEG shows mild brain suffering in acute phase. Brain MRI showed mild hypomyelination and reduced thickness of the corpus callosum for his age; spectroscopy did not show any evidence of lactate (see report). 3rd episode of rhabdomyolysis (28 months old).
After 4 weeks of hospitalization CK that was back to normal values (147) but he took a viral infection (adenovirus). He had high temperature and cough. CK started to rise again up to 54,000 (ul/L) as well as CK-MB and Troponin T.
During this episode the following were observed:
• The heart was severely affected and had a cardiogenic shock (with cardiac arrest).
• He was in high intensive care for two weeks under heavy drug treatment (adrenaline, morphine etc).
• A nasogastric tube was placed for feeding.
• Several weeks after heart failure, he slowly started back to move and regained some strengths.

Now, July 2017 (3 years old -10 months after discharge from hospital)
He has done progresses both form motor and cognitive aspects.
• Motor development: he is again able to crawl and stand up and move some steps with support.
• Cognitive development: He does understand basic questions and replies with yes / no shaking his head. He does a bit of lallation, and He is able to say “Mum”, dad and couple of other simple words.