megdel ( 3-methylglutaconic aciduria with deafness , encephalopathy , and leigh - like syndrome ) syndrome is a mitochondrial disorder associated with recessive mutations in serac1 . this 7  year - old girl was the first child of consanguineous turkish parents . symptoms and biological findings progressively improved with symptomatic treatment but lactic acidosis and high lactate to pyruvate ratio along with 3-methylglutaconic aciduria persisted . at 8  months of age , a subacute neurological degradation occurred with severe hypotonia , dystonia with extrapyramidal movements and failure to thrive . brain mri revealed basal ganglia lesions suggestive of leigh syndrome . at 3  years of age megdel syndrome was further confirmed by the identification of an already reported homozygous mutation in serac1 . transient neonatal polyuria and renal failure have not been reported to date in serac1 defective patients . megdel ( 3-methylglutaconic aciduria with deafness , encephalopathy , and leigh - like syndrome , mim 614739 ) syndrome is a recessively inherited disorder recently associated with recessive mutations in serac1 
 . serac1 ( serine active site containing 1 ) is a protein involved in phosphatidylglycerol remodeling located in the mitochondrial - associated membrane at the contact site between endoplasmic reticulum and mitochondria . the identification of serac1 mutations in megdel syndrome helped defining a new category of nuclear - encoded mitochondrial - related diseases , namely genetic defects of phospholipid biosynthesis , remodeling and metabolism , , , , . such new category of mitochondrial - related inborn errors of phospholipid metabolism became clearly identifiable with the recent application of next generation sequencing methodologies . these diseases include taz mutations ( barth syndrome ) , dnajc19 ( dcma syndrome ) , serac1 mutations ( megdel syndrome ) , agk mutations ( sengers syndrome ) , ddhd1 and ddhd2 mutations ( hereditary spastic paraplegia ) . in taz , serac1 , dnajc19 and agk mutations , 3-methylglutaconic aciduria ( 3-mga ) we report herein transient kidney features in a neonate later diagnosed with megdel syndrome . this first girl from consanguineous healthy turkish parents was born at 39  weeks of gestation by caesarean section because of fetal bradycardia . birth weight , height and head circumference were 2.200  kg , 45  cm , and 31  cm respectively , ( <  3rd percentile ) . , she was admitted to the intensive care unit for respiratory failure and tachycardia along with truncal hypotonia and tremor . labs showed metabolic acidosis with increased anion gap due to hyperlactatemia ( 19.8  mm , normal value <  2.5  mm ) , moderately elevated ammonia level ( 186  m , normal value <  90  m ) , moderately increased liver enzymes ( 1.5 fold ) and cpk ( 1600 iu / l , normal value <  800 ) and transient liver failure ( protrombin time 29% , factor v 28% ) . she also exhibited hypernatremic dehydration ( there was a decrease of 140  g compared to birth weight and blood sodium was 150  mm , normal value <  145  mm ) , renal failure with increased serum creatinine ( 95  m , normal range 2580  m ) and massive polyuria ( maximum diuresis 15  ml / kg / h , normal range 25  ml / kg / h ) with hyperlactaturia ( lactate to creatinine ratio of 1.6  mmol / mmol , normal value <  0.1 ) . there was no sign of proximal tubular dysfunction . urine osmolality was low ( 192  mosm / kg ; reference range : 500800  mosm / kg ) . sustained urinary excretion of 3-mga was noted but exact values could not be quantified due to elevated lactate excretion . thanks to symptomatic intravenous compensation of urinary water losses ( initial daily fluid intake : 225  ml / kg / day ; sodium intake : 15  meq / kg / day ) , renal abnormalities disappeared within 3  days . from the age of 8  months , she exhibited failure to thrive along with head circumference growth arrest . psychomotor milestones were delayed and truncal hypotonia with left eye strabismus were noted . at 15  months of age , her weight , height and head circumference were 7.250  kg ( <   2.5  sd ) , 74.5  cm ( <   0.5  sd ) and 44.5  cm ( <   2  sd ) respectively . clinical examination revealed axial hypotonia , with pyramidal signs , strabismus and left amblyopia associated with hypermetropia . labs showed a 2-fold increase of liver enzymes and high lactate in blood ( maximum in the fed state at 5.4  mm , normal value <  2  mm ) and cerebrospinal fluid ( 3.20  mm , normal <  2  mm ) with elevated csf lactate to pyruvate ratio ( 16 , normal <  12 ) . a second brain mri disclosed symmetrical and bilateral hyperintensities in the caudate nuclei and putamina associated with cerebellar atrophy ( reported in ) . urinary 3-mga excretion persisted . from 3  years of age , severe dystonia , spastic tetraparesis and hearing loss audiometry revealed bilateral sensorineural deafness , which was severe on the right side and profound on the left side . speech development was absent and motor development milestones severely delayed but rigorous assessment of neurodevelopment could not be performed . the patient is currently 7  years and 9  months old and exhibits a severe and slowly progressive dystonic encephalopathy with correct growth parameters ( weight :   0.5  sd , height : 0  sd ) due to improvement of the caloric intake . renal function ( as assessed by serum creatinine ) is normal and there is no polyuria . mitochondrial respiratory chain activities were normal in skin fibroblasts and skeletal muscle ( not shown ) . whole exome sequencing had been performed just before the identification of the molecular basis of megdel syndrome ( i.e. description of serac1 mutations ) and found an already reported homozygous mutation in serac1 
 . this mutation ( c.1822_1828  +  10del17ins9 ) was confirmed by sanger sequencing with appropriate parental segregation . this first girl from consanguineous healthy turkish parents was born at 39  weeks of gestation by caesarean section because of fetal bradycardia . birth weight , height and head circumference were 2.200  kg , 45  cm , and 31  cm respectively , ( <  3rd percentile ) . , she was admitted to the intensive care unit for respiratory failure and tachycardia along with truncal hypotonia and tremor . labs showed metabolic acidosis with increased anion gap due to hyperlactatemia ( 19.8  mm , normal value <  2.5  mm ) , moderately elevated ammonia level ( 186  m , normal value <  90  m ) , moderately increased liver enzymes ( 1.5 fold ) and cpk ( 1600 iu / l , normal value <  800 ) and transient liver failure ( protrombin time 29% , factor v 28% ) . she also exhibited hypernatremic dehydration ( there was a decrease of 140  g compared to birth weight and blood sodium was 150  mm , normal value <  145  mm ) , renal failure with increased serum creatinine ( 95  m , normal range 2580  m ) and massive polyuria ( maximum diuresis 15  ml / kg / h , normal range 25  ml / kg / h ) with hyperlactaturia ( lactate to creatinine ratio of 1.6  mmol / mmol , normal value <  0.1 ) . there was no sign of proximal tubular dysfunction . urine osmolality was low ( 192  mosm / kg ; reference range : 500800  mosm / kg ) . sustained urinary excretion of 3-mga was noted but exact values could not be quantified due to elevated lactate excretion . thanks to symptomatic intravenous compensation of urinary water losses ( initial daily fluid intake : 225  ml / kg / day ; sodium intake : 15  meq / kg / day ) , renal abnormalities disappeared within 3  days . from the age of 8  months , she exhibited failure to thrive along with head circumference growth arrest . psychomotor milestones were delayed and truncal hypotonia with left eye strabismus were noted . at 15  months of age , her weight , height and head circumference were 7.250  kg ( <   2.5  sd ) , 74.5  cm ( <   0.5  sd ) and 44.5  cm ( <   2  sd ) respectively . clinical examination revealed axial hypotonia , with pyramidal signs , strabismus and left amblyopia associated with hypermetropia . labs showed a 2-fold increase of liver enzymes and high lactate in blood ( maximum in the fed state at 5.4  mm , normal value <  2  mm ) and cerebrospinal fluid ( 3.20  mm , normal <  2  mm ) with elevated csf lactate to pyruvate ratio ( 16 , normal <  12 ) . a second brain mri disclosed symmetrical and bilateral hyperintensities in the caudate nuclei and putamina associated with cerebellar atrophy ( reported in ) . urinary 3-mga excretion persisted . from 3  years of age , severe dystonia , spastic tetraparesis and hearing loss audiometry revealed bilateral sensorineural deafness , which was severe on the right side and profound on the left side . speech development was absent and motor development milestones severely delayed but rigorous assessment of neurodevelopment could not be performed . the patient is currently 7  years and 9  months old and exhibits a severe and slowly progressive dystonic encephalopathy with correct growth parameters ( weight :   0.5  sd , height : 0  sd ) due to improvement of the caloric intake . renal function ( as assessed by serum creatinine ) is normal and there is no polyuria . mitochondrial respiratory chain activities were normal in skin fibroblasts and skeletal muscle ( not shown ) . whole exome sequencing had been performed just before the identification of the molecular basis of megdel syndrome ( i.e. description of serac1 mutations ) and found an already reported homozygous mutation in serac1 
 . this mutation ( c.1822_1828  +  10del17ins9 ) was confirmed by sanger sequencing with appropriate parental segregation . however , some additional , initially undescribed features were reported such as neonatal hepatopathy , optic nerve atrophy , microcephaly , and myoclonic epilepsy . none of the 3 reported patients harboring the same mutation than our patient exhibited similar neonatal kidney abnormalities . however , unlike our patient , these 3 patients were not homozygous but compound heterozygous for this mutation . therefore , no strict genotype - phenotype correlation can be made between these 3 patients and ours . accordingly , the data reported here suggest that such transient renal findings were not due to the severity of the clinical deterioration but could rather be probably ascribable to a specific defect related to serac1 dysfunction in the neonatal kidney . more specifically , severe neonatal hypoxic ischemic conditions can show kidney damage usually expressed by acute tubular necrosis and not by massive polyuria . in keeping with this , the fact that exome sequencing did not identify any recessive mutation in other genes does not support the role for another recessive disorder at the origin of these kidney findings . most of the reported serac1 patients exhibited defective respiratory chain activities in cultured skin fibroblasts and/or skeletal muscle , which was surprisingly not the case for our patient . the exact function of serac1 has not been fully elucidated yet and the impact of serac1 dysfunction on mitochondrial respiratory chain function has not been clarified . interplay of serac1 with intracellular cholesterol metabolism has been suggested as filipin testing showed abnormal results related to accumulation of intracellular unesterified cholesterol as observed in niemann - pick type c disease . another unsolved issue concerns the role for 3-mga urinary excretion in some of these mitochondrial defects of complex lipids biosynthesis and remodeling . to date , 3-mga is definitely a biomarker for these defects   but its role in the pathophysiology of megdel remains to be elucidated . 3-mga could probably be viewed as a biomarker for inborn errors involving a disruption of the architecture of the mitochondrial membranes , . renal disease may be observed in neonatal mitochondrial respiratory chain diseases that usually present with severe proximal tubular dysfunction or nephrotic syndrome   but transient water loss and kidney failure were not reported in neonatal mitochondrial diseases . to conclude , massive polyuria with low urine osmolality and transient neonatal renal failure widens the spectrum and further delineates the phenotype of megdel syndrome for which only 30 to 40 patients are known . in the setting of a neonatal deterioration with lactic acidosis and 3-mga , such renal findings should be searched for and if present prompt the clinician to perform molecular analysis of serac1 . all procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation ( institutional and national ) and with the helsinki declaration of 1975 , as revised in 2000 . details of the contributions of individual authors carole harbulot analyzed the data and wrote the paper .
backgroundmegdel ( 3-methylglutaconic aciduria with deafness , encephalopathy , and leigh - like syndrome ) syndrome is a mitochondrial disorder associated with recessive mutations in serac1.objectivesto report transient neonatal renal findings in megdel syndrome.resultsthis 7  year - old girl was the first child of consanguineous turkish parents . 
 she exhibited an acute neonatal deterioration with severe lactic acidosis and liver failure . 
 initial evaluation revealed massive polyuria and renal failure with 3-methylglutaconic aciduria . 
 symptoms and biological findings progressively improved with symptomatic treatment but lactic acidosis and high lactate to pyruvate ratio along with 3-methylglutaconic aciduria persisted . at 8  months of age , 
 a subacute neurological degradation occurred with severe hypotonia , dystonia with extrapyramidal movements and failure to thrive . 
 brain mri revealed basal ganglia lesions suggestive of leigh syndrome . at 3  years of age , 
 sensorineural deafness was documented . 
 megdel syndrome was further confirmed by the identification of an already reported homozygous mutation in serac1.conclusiontransient neonatal polyuria and renal failure have not been reported to date in serac1 defective patients . such neonatal kidney findings expand the clinical spectrum of megdel syndrome .