Mutation in the Neuroblastoma Amplified Sequence Gene as a Cause of Recurrent Acute Liver Failure, Acute Kidney Injury, and Status Epilepticus

Abstract

Cause of acute liver failure (ALF) in children remains elusive in almost 50% cases. It is caused by viral hepatitis, hemophagocytic lymphohistiocytosis, autoimmune diseases, drugs, and metabolic diseases. Recurrent ALF with intermittent recovery is caused by metabolic disorders such as fatty acid oxidation defects, respiratory chain disorders, or unknown repeat insult from diet, toxins, or viruses. Biallelic mutations in the neuroblastoma amplified sequence (NBAS) gene have recently been associated with infantile liver failure syndrome type 2. It is associated with ALF during intercurrent febrile illness and complete recovery with conservative management. A 12-year-old boy presented with history of recurrent ALF since infancy with complete recovery and no etiological clue. He was detected to have homozygous pathogenic variation in NBAS gene which has been recently described in the literature to be associated with recurrent ALF. This is the first such case report from India. During the episode of ALF, when he presented to us, he had acute kidney injury and status epilepticus. The association of other organs with NBAS protein deficiency–associated ALF needs to be established.

A 12-year-old male child born of third degree consanguineous marriage presented in the emergency room with dehydration, hematemesis following 2 days of moderate fever. On admission, he appeared dull but was conscious and oriented with a heart rate of 140/min and blood pressure of 110/60 mm Hg. He had mild dehydration and tender hepatomegaly of 5 cm, and there was no involvement of other systems. His growth parameters were normal.

He had a past history of recurrent episodes of acute liver failure (ALF) since infancy, precipitated by fever, followed by complete recovery. Table 1 gives a summary of clinical and laboratory parameters during previous episodes. While he was hospitalized elsewhere, he had been extensively investigated for etiologies such as infections, autoimmune hepatitis, Wilson disease, fructose intolerance, mitochondrial and fatty acid disorders, and toxins, but clinical and biochemical profiles were inconclusive. During one such episode at the age of 5 years, magnetic resonance image (MRI) of the brain was normal, and liver biopsy (LB) showed few hepatocytes with ballooning degeneration, microvesicular steatosis, and mild lymphocytic infiltration with mild interstitial fibrosis. He had normal growth and development with a good scholastic record. There was no positive family history, facial dysmorphism, and systemic abnormalities.

Table 1.

Summary of Clinical and Laboratory Parameters During Previous ALF Episodes.

Sr. No.	Age at presentation	Clinical features	Liver enzymes (AST/ALT) (IU/L)	Bilirubin (total/direct) (mg/dl)	Other investigations	Clinical recovery
1	1 year and 3 months	Viral upper respiratory tract infection, pain in abdomen	-/400	4.9/4.1	Serum creatinine, blood urea nitrogen, and serum electrolytes are normal.	Recovered over 7 days
2	5 years	Fever, vomiting for 1 day, followed by altered sensorium for a week, hepatomegaly documented	788/592 (INR-1)	4.6/1.4	Urine reducing substances, negative. Serum ceruloplasmin, 16.3 mg/dL (normal 20–65), and urine copper were normal	Liver enzymes normal over 20 days
3	7 years	Enteric fever, hepatomegaly	1456/885 (INR-1)	0.6/0.3	Anti–hepatitis A, B, and C antibody tests were normal. Renal function tests were normal. Wilson disease workup was again normal.	Liver enzymes normal over few days
4	10 years	Fever, vomiting, mild altered sensorium	7335/4687	4.7/2.9		Normal over 5 days

ALF, acute liver failure; ALT, alanine aminotransferase, AST, aspartate aminotransferase; INR, international normalized ratio.

Within a few hours of current admission, the patient became drowsy with nasal bleeding and had hypoglycemia with deranged metabolic profile (Table 2). With ventilatory support, intravenous fluids, and management of coagulopathy, clinical condition became stable, blood sugar was normal, and bleeding stopped within 48 h. But after 72 h, he had worsening acidosis (blood gases showing pH 7.260, pCO₂ 40.3, pO₂ 185.9, HCO₃ 17.6) and worsening renal parameters, requiring hemodialysis. Following this, by the 6th day of admission, he started maintaining normal blood sugar levels, renal parameters, and coagulation profile. He was managed by fluid resuscitation, vasopressors, fresh frozen plasma, 3% NaCl (for raised intracranial pressure), hepatoprotective measures (N-acetylcystine infusion), antibiotics, and vitamins. On day 7, he had recurrent seizures with MRI of the brain (Figure 1) showing microhemorrhages and required management of refractory epilepsy with multiple antiepileptics.

Table 2.

Investigation Profile During Current Admission of the Patient.

Investigations	Day 1	Day 3	Day 5	Day 10	Day 20
Hemoglobin (gm %)	12.4	9.9	9.2	8.8	9.1
Total leukocyte count (per cmm)	9600	4700	7200	18000	4700
Platelet count (per cmm)	140000	107000	140000	130000	240000
Blood sugar (mg/dl)	58	120
ALT (IU/L)	9500	2400	500	–	120
AST (IU/L)	4600	2100	320	–	150
GGTP (U/L)	1364
Bilirubin (total/direct) (mg/dl)	2.3/2
Albumin (3.8–5.4 g/dL)	3.2
Globulin (2–3.5 g/dL)	4.5
Alkaline phosphatase (<300 U/L)	425
INR	>5	1.9	1.3	–	1.2
Ammonia (normal<30 umol/L)	150	60	–	–	–
Lactate (normal<2 mmol/L)	4	1.2	–	–	–
Blood urea nitrogen (normal 5–25 mg/dl)	50	90	104	32	12
Serum creatinine (mg/dl)	2.6	6.3	9.1	2.4	0.7
Urine	Normal. Reducing substances negative.
Serum immunoglobulin G level (normal 650–1620 mg/dL)	1170
Antinuclear antibodies (normal less than 1)	0.277
Liver kidney microsome antibodies (LKM1)	Negative
Tandem mass spectrometry(TMS)	Total carnitine normal. Free carnitine–to–acyl carnitine ratio normal. Mild elevation in levels of few acylcarnitines such as butyryl/isobutyryl (C4), propionyl (C3), and acetyl (C2) and amino acids such as alanine, methionine, and phenylalanine (abnormalities were reported to be indicative of mitochondrial disorder)
Urine gas chromatography–mass spectrometry (GC/MS)	Lactate, pyruvate, 4-hydroxyphenyl lactate, and pyruvate levels elevated and ketones normal
2D echocardiography and detailed ophthalmic examination including slit lamp and fundus were normal

ALT, alanine aminotransferase; AST, aspartate aminotransferase; GGTP, gamma-glutamyl transpeptidase; INR, international normalized ratio.

Figure 1.

MRI of brain showing microhemorrhages.

Metabolic workup showed few abnormal acylcarnitines and amino acids, indicative of mitochondrial disease (Table 2). Ultrasonography of the abdomen showed mild fatty liver but absence of portal hypertension or chronic liver disease. Clinical condition was stable after 10 days, but complete recovery took 4 weeks without any neurological or systemic complications. Exome sequencing and mitochondrial genome sequencing was performed, which revealed pathogenic homozygous missense variation (chr2:15651460C > T; c.761G > A; p.Gly254Asp) in the neuroblastoma amplified sequence (NBAS) gene. A carrier study of the parents confirmed the same heterozygous pathogenic variation. During follow-up at 3 months, he had gradual complete clinical, biochemical recovery and did not require any additional treatment.

Discussion

ALF in children is a life-threatening complication, and the prognosis is often guarded. Sometimes, liver transplantation (LT) is the only lifesaving option. The etiology is indeterminate in almost 50% cases.¹ Recurrent ALF with intermittent complete recovery may be caused by infections, immunological diseases, toxins, metabolic liver diseases such as fructose intolerance, mitochondrial energy defects such as respiratory chain disorders, fatty acid oxidation defects, carnitine cycle, and dihydrolipoamide dehydrogenase (E3) deficiency, as discussed by Alam et al² It is important to identify the cause as metabolic disorders with multisystem involvement may not improve after LT, whereas simple metabolic intervention can help in some others. Biallelic mutations in the NBAS gene have recently been associated with infantile liver failure syndrome type 2. There was ALF during intercurrent febrile illness with complete recovery, whereas investigations during the asymptomatic period are normal.³ Narkewicz et al⁴ described that lack of diagnosis may be due to death, incomplete/inconclusive metabolic workup, or lack of search for rare causes. Besides coagulopathy, multisystemic complications contraindicate LB in many cases, but sometimes, the transjugular route may be used. The role of LB in ALF is limited, except in some cases of autoimmune hepatitis and Wilson disease, and diagnostic yield may not be increased.⁵ Our case consistently showed negative workup for all diagnosable causes of recurrent ALF. Here, we must consider pitfalls of metabolic investigations as findings similar to those of metabolic diseases may be present in a setting of ALF and have to be carefully interpreted.⁶ Chronic acetaminophen–associated liver injury is rare but still has to be considered.⁷ Haack et al³ studied clinical, genetic, and biochemical characteristics in patients with previously unclassified recurrent ALF and concluded that NBAS mutations should be studied in such patients. It differs from other causes as it is precipitated by fever, and these patients show complete recovery in the intervening period; hence, it should be suspected in such clinical scenarios. NBAS protein is thought to function as a component of the endoplasmic reticulum (ER) tethering complex, and it is proposed that catabolic state and high energy demand during fever impairs function because of thermal susceptibility of the syntaxin 18 complex, resulting in ER stress, but exact mechanism remains unclear. Some patients had comorbidities such as cardiomyopathy and gastrointestinal, renal, and neurological involvement. Our patient had significant acute kidney injury, requiring dialysis, and status epilepticus, the cause of which could not be explained, including drugs and had complete recovery. With current available evidence, prompt management of the underlying cause of fever and acute liver crisis can be suggested. Failure of these measures may further suggest role of LT, but its use in prevention of further episodes and prognosis after LT is yet unclear; there is insufficient evidence in the literature. A case reported by Nadezda et al⁷ required LT during one of the fulminant crisis, but final diagnosis was later confirmed. Specific interventions for prevention of onset of liver failure during fever episode need to be determined. Our patient did not have any evidence of congenital systemic abnormalities and syndromic features. NBAS has been associated with a syndrome of short stature and cone and optic nerve atrophy (Pelger–Huet anomaly) in the Yakut population.⁸ ALF caused by NBAS deficiency and this syndrome are different clinical entities. Patients with this syndrome do not have any liver disease manifestation. Genetic findings and evolving phenotype–genotype correlations will continue to expand our understanding in many unexplained etiologies of liver diseases. It helps us in explaining prognosis, management, and careful selection of patients for LT. In view of severe presentation in our case, role of preventive measures and feasibility of LT should further be discussed in the light of current evidence.

In conclusion, NBAS gene mutations should be considered as a cause of recurrent ALF. Mutations in this gene may cause not only an isolated hepatic involvement but also a multisystem disease which need to be characterized further and should be kept in mind during the course of the illness.

Conflicts of interest

The authors have none to declare.

funding

None.