Maleic acid is a biomarker for maleylacetoacetate isomerase deficiency; implications for newborn screening of tyrosinemia type 1.

Dried blood spot succinylacetone (SA) is often used as a biomarker for newborn screening (NBS) for tyrosinemia type 1 (TT1). However, false-positive SA results are often observed. Elevated SA may also be due to maleylacetoacetate isomerase deficiency (MAAI-D), which appears to be clinically insignificant. This study investigated whether urine organic acid (uOA) and quantitative urine maleic acid (Q-uMA) analyses can distinguish between TT1 and MAAI-D. We reevaluated/measured uOA (GC-MS) and/or Q-uMA (LC-MS/MS) in available urine samples of nine referred newborns (2 TT1, 7 false-positive), eight genetically confirmed MAAI-D children, and 66 controls. Maleic acid was elevated in uOA of 5/7 false-positive newborns and in the three available samples of confirmed MAAI-D children, but not in TT1 patients. Q-uMA ranged from not detectable to 1.16 mmol/mol creatinine in controls (n = 66) and from 0.95 to 192.06 mmol/mol creatinine in false-positive newborns and MAAI-D children (n = 10). MAAI-D was genetically confirmed in 4/7 false-positive newborns, all with elevated Q-uMA, and rejected in the two newborns with normal Q-uMA. No sample was available for genetic analysis of the last false-positive infant with elevated Q-uMA. Our study shows that MAAI-D is a recognizable cause of false-positive TT1 NBS results. Elevated urine maleic acid excretion seems highly effective in discriminating MAAI-D from TT1.

Clinical and diagnostic approach in unsolved CDG patients with a type 2 transferrin pattern.

Dysmorphic features, multisystem disease, and central nervous system involvement are common symptoms in congenital disorders of glycosylation, including several recently discovered Golgi-related glycosylation defects. In search for discriminative features, we assessed eleven children suspected with a Golgi-related inborn error of glycosylation. We evaluated all genetically unsolved patients, diagnosed with a type 2 transferrin isofocusing pattern in the period of 1999-2009. By combining biochemical results with characteristic clinical symptoms, we used a diagnostic flow chart to approach the underlying defect in patients with congenital disorders of glycosylation-IIx. According to specific symptoms and laboratory results, we initiated additional, targeted biochemical and genetic studies. We found a distinctive spectrum of congenital disorders of glycosylation type 2-associated anomalies including sudden hearing loss, brain malformations, wrinkled skin, and epilepsy in combination with skeletal dysplasia, dilated cardiomyopathy, sudden cardiac arrest, abnormal copper and iron metabolism, and endocrine abnormalities in our patients. One patient with severe cortical malformations and mild skin abnormalities was diagnosed with a known genetic syndrome, due to an ATP6V0A2 defect. Here, we present unique congenital disorders of glycosylation type 2-associated anomalies, including both ATPase-related and unrelated cutis laxa and sensorineural hearing loss, a recently recognized symptom of congenital disorders of glycosylation. Based on our findings, we recommend clinicians to consider congenital disorders of glycosylation in patients with cardiac rhythm disorders, spondylodysplasia and biochemical abnormalities of the copper and iron metabolism even in absence of intellectual disability.

Recurrent thrombo-embolism in a child with a congenital disorder of glycosylation (CDG) type Ib and treatment with mannose.

Thrombosis is a multifactorial disorder. Congenital disorders of glycosylation (CDG) are one of the known risk factors for its occurrence. These disorders result in glycosylation defects of glycoproteins, including those of the (anti-)coagulation system. CDG-Ib can specifically be treated with mannose, as illustrated by the case of a 4-year-old girl in whom deep venous thrombosis was the presenting symptom after a common viral infection. The diagnosis was made after recurrent episodes of thrombo-embolism and consumptive coagulopathy. After treatment with mannose no such episodes recurred. The pathophysiology of CDG as a risk factor for thrombotic disease is discussed.

Muscular glycogen storage diseases without increased glycogen content on histopathological examination.

Histopathological findings of muscle biopsies from five patients with two different muscular glycogen storage diseases (mGSD) were presented. From these investigations it emerged that the yield of histopathology in mGSD is low. In only one of five patients histopathological findings gave a clue towards diagnosis. It can be concluded that non-specific findings or even normal appearance of a muscle biopsy does not exclude mGSD.

Tyrosinemia type I treated by NTBC: how does AFP predict liver cancer?

BACKGROUND: Tyrosinemia type I is associated with an increased risk of liver cancer development. The formation of the pathogenic fumarylacetoacetate is prevented by 2-(2-nitro-4-3 trifluoro-methylbenzoyl)-1,3-cyclohexanedione (NTBC). Still, some patients with NTBC treatment develop liver cancer. A rise of alpha-fetoprotein (AFP) is an indicator of liver cancer. AIM: To study the predictive value of AFP in tyrosinemia type I patients for the discrimination between patients at high and low risk of liver cancer development. METHODS: We examined the course of AFP values of 11 Dutch patients with tyrosinemia type I treated by NTBC, of whom four were diagnosed with liver cancer. RESULTS: The four patients with liver cancer had a course of AFP different from the other patients in either velocity of the decrease of AFP, achieving normal AFP and/or having a rise of AFP concentrations. CONCLUSION: Apart from a rise of AFP, a slow AFP decrease, and never normalizing levels of AFP are important predictors of liver cancer development in further life.

Renal function in tyrosinaemia type I after liver transplantation: a long-term follow-up.

Hereditary tyrosinaemia type I is an autosomal recessive inborn error of tyrosine catabolism caused by a deficiency of the enzyme fumarylacetoacetase that results in liver failure, hepatocellular carcinoma, renal tubular dysfunction and acute intermittent porphyria. When treated with liver transplantation, tyrosinaemia type I was considered to be cured. Some years after the first liver transplantations in these patients, some reports focused on the renal function after transplantation. These reports showed that urinary succinylacetone excretion remained but that tubular function normalized. In this report we discuss the long-term renal follow-up (mean follow-up time 11 years, range 7-14 years) after liver transplantation in 9 patients with tyrosinaemia type I treated by liver transplantation in our centre. An evaluation was made of renal function and succinylacetone excretion in urine. In all patients we found a persistent excretion of succinylacetone in the urine. With respect to the glomerular function, we can conclude that there is no clear change in GFR. At the same time, tubulopathy persisted in some patients. We consider that excretion of metabolites such as succinylacetone will be an important contributing factor to tubular dysfunction after liver transplantation in patients with tyrosinaemia type I. Therefore, notwithstanding the major effect of liver transplantation on tyrosine metabolism, renal tubular dysfunction remains at risk and needs careful monitoring. Progressive tubular dysfunction can cause glomerular damage. The use of low-dose NTBC might be considered after liver transplantation in case of tubulopathy to prevent progression of tubular and glomerular dysfunction.

Liver transplantation in mitochondrial respiratory chain disorders.

UNLABELLED: Mitochondrial respiratory chain disease may lead to neonatal or late onset liver failure, requiring liver transplantation. In rare cases, the disease is restricted to the liver and the patient is cured after surgery. More frequently, other organs are simultaneously involved and neuromuscular or other extra-hepatic symptoms may pre-exist, or appear in the post-transplant follow up. Pre-transplant evaluation should aim to rule out neurological disease, which may be difficult to differentiate from signs accompanying liver insufficiency. Cerebrospinal fluid lactic acid levels, compared to blood lactate, may be suggestive of central nervous system involvement. Of 11 cases with respiratory chain disorders who had liver transplantation in various centres, 4 are alive and well on follow up, and 6 died, three of them having developed neurological disease post orthotopic liver transplantation. All three patients with initial liver and gastro-intestinal disease died early after transplantation, indicating that these may be poor candidates for this procedure. CONCLUSION: Liver transplantation is feasible in hepatic respiratory chain disorders, but extra-hepatic disease should be ruled out before transplantation. Extra-hepatic manifestations may, however, appear and cause patient death despite successful transplantation.

Hereditary tyrosinemia type I: a new clinical classification with difference in prognosis on dietary treatment.

Hereditary tyrosinemia type I (McKusick 27670) is a heterogeneous disease with poor prognosis, yet there are few reports of the long-term prognosis. It is therefore difficult to decide on the treatment for individual patients. We have conducted an international survey of patients with tyrosinemia type I and examined the probability of survival on dietary treatment and the causes of death in 108 patients with tyrosinemia type I. The survival after the onset of symptoms varied with the age at onset; the earlier the symptoms developed the poorer the outlook. Liver failure and recurrent bleeding (67%), hepatocellular carcinoma (17%) and the porphyria-like syndrome with respiratory failure (10%) were the most common causes of death. The 1- and 2-yr survival probability after the onset of symptoms in patients in whom symptoms developed before 2 mo, between 2 and 6 mo and after 6 mo were 38%/29%, 74%/74% and 96%/96%, respectively. On the basis of these survival rates, a new classification--which is important with respect to choices in treatment--is proposed: very early (onset of symptoms < 2 mo), early (2 to 6 mo) and late presenting form (> 6 mo).