Inborn Error Of Lipid Metabolism Research Articles

Sjögren–Larsson Syndrome (SLS) - A Case Report

Introduction: Sjogren Larsson syndrome (SLS) is a rare autosomal recessive inborn error of lipid metabolism. The classical triad of ichthyosis, mental retardation and spasticity characterizes clinical features. There are only 200 cases reported worldwide. Aim: To report 3 cases from the same family and the index patient having a classical presentation. Case: Eldest female and two males, who display congenital ichthyosis, whose parents have no such symptoms. Both males complained of diffuse scales all over the body with mild erythema and severe itching, since birth, no history of blisters was present. Nails, teeth, hair and sweating were normal. They had itching all over the body with accentuation over flexural areas. The youngest has neurological as well as psychiatric problems as Bipolar disorder. Discussion: Mental retardation is common, depressive episodes are a common sequlae, however clear bipolar illness is not reported. Some behavioral phenotypes of ADHD have been reported in the literature . Seizures are commonly reported, however our index patient did not have any history. Most studies on icthyosis give a similar picture as above cases.

Sjögren-Larsson syndrome: The mild end of the phenotypic spectrum.

Sjögren‐Larsson syndrome (SLS) is a rare inborn error of lipid metabolism. The syndrome is caused by mutations in the ALDH3A2 gene, resulting in a deficiency of fatty aldehyde dehydrogenase. Most patients have a clearly recognizable severe phenotype, with congenital ichthyosis, intellectual disability, and spastic diplegia. In this study, we describe two patients with a remarkably mild phenotype. In both patients, males with actual ages of 45 and 61 years, the diagnosis was only established at an adult age. Their skin had been moderately affected from childhood onward, and both men remained ambulant with mild spasticity of their legs. Cognitive development, as reflected by school performance and professional career, had been unremarkable. Magnetic resonance spectroscopy of the first patient was lacking the characteristic lipid peak. We performed a literature search to identify additional SLS patients with a mild phenotype. We compared the clinical, radiologic, and molecular features of the mildly affected patients with the classical phenotype. We found 10 cases in the literature with a molecular proven diagnosis and a mild phenotype. Neither a genotype‐phenotype correlation nor an alternative explanation for the strikingly mild phenotypes was found. New biochemical techniques to study the underlying metabolic defect in SLS, like lipidomics, may in the future help to unravel the reasons for the exceptionally mild phenotypes. In the meantime, it is important to recognize these mildly affected patients to provide them with appropriate care and genetic counseling, and to increase our insights in the true disease spectrum of SLS.

Persistent dyslipidemia in treatment of lysosomal acid lipase deficiency

BackgroundLysosomal acid lipase deficiency (LALD) is an autosomal recessive inborn error of lipid metabolism characterized by impaired lysosomal hydrolysis and consequent accumulation of cholesteryl esters and triglycerides. The phenotypic spectrum is diverse, ranging from severe, neonatal onset failure to thrive, hepatomegaly, hepatic fibrosis, malabsorption and adrenal insufficiency to childhood-onset hyperlipidemia, hepatomegaly, and hepatic fibrosis. Sebelipase alfa enzyme replacement has been approved by the Food and Drug Administration for use in LALD after demonstrating dramatic improvement in transaminitis and dyslipidemia with initiation of enzyme replacement therapy.MethodsA chart review was performed on 2 patients with childhood-onset, symptomatic LALD with persistent dyslipidemia despite appropriate enzyme replacement therapy to identify biological pathways and risk factors for incomplete response to therapy.ResultsTwo patients with attenuated, symptomatic LALD had resolution of transaminitis on enzyme replacement therapy without concomitant effect on dyslipidemia despite dose escalation and no evidence of antibody response to enzyme.ConclusionEnzyme replacement therapy does not universally resolve all complications of LALD. Persistent dyslipidemia remains a clinically significant issue, likely related to the complex metabolic pathways implicated in LALD pathogenesis. We discuss the possible mechanistic basis for this unexpected finding and the implications for curative LALD therapy.

Sjogren-Larsson Syndrome: Mechanisms and Management.

Sjogren Larsson syndrome (SLS) is a rare autosomal recessive inborn error of lipid metabolism due to mutations in the ALDH3A2 that result in a deficiency of fatty aldehyde dehydrogenase (FALDH). The syndrome has a high prevalence in Sweden where it was first described, but now known to occur worldwide. The classical triad of ichthyosis, mental retardation and spasticity characterizes clinical features. Preterm birth is common. “Glistening white dots” in the retina is a pathognomic clinical feature. Magnetic resonance imaging of the brain demonstrates leukoencephalopathy predominant in the periventricular region. Cerebral MR spectroscopy reveals a characteristic abnormal lipid peak at 1.3ppm and a small peak at 0.9ppm. The primary role of FALDH is oxidation of medium and long-chain aliphatic aldehydes derived from fatty alcohol, phytanic acid, ether glycerolipids and sphingolipids. The diagnosis is based on the typical phenotype, demonstration of the enzyme deficiency and presence of biallelic mutations in the ALDH3A2. The management of SLS largely remains symptomatic currently. However, several potential therapeutic options are being developed, keeping in view of the fundamental metabolic defects or correcting the genetic defect. This review aims to summarize the clinical, genetic and biochemical findings, pathogenetic mechanisms and the current therapeutic options, in SLS.

Genetic assessment of ten Egyptian patients with Sjögren-Larsson syndrome: expanding the clinical spectrum and reporting a novel ALDH3A2 mutation.

Assessment of ten Egyptian patients with Sjögren-Larsson syndrome (SLS) detected; unusual clinical manifestations, a first report of brain atrophy in SLS, some patients exhibited neither retinal dots nor white matter changes previously reported as essential manifestations. We identified five mutations in ALDH3A2 gene including a novel one and suggest a founder effect. Sjögren-Larsson syndrome is a rare autosomal recessive inborn error of lipid metabolism caused by mutations in the ALDH3A2 gene that codes for fatty aldehyde dehydrogenase and result in a triad of ichthyosis, spasticity, and mental retardation. Clinical, radiological, biochemical, and neurophysiological evaluation in ten SLS patients descending from seven unrelated Egyptian pedigrees was followed by Sanger sequencing of ALDH3A2 performed by ABI 3500. All patients presented with SLS triad; ichthyosis, spasticity of four limbs and hyperreflexia with an intelligent quotient (IQ) ranging from (39 to 69). Other manifestations were dysmorphic features, seizures, and skeletal and ophthalmological affection. Mutational analysis of ALDH3A2 gene revealed three missense, one splice site, and one novel stop codon mutation; c.991G>T (p.E331X). Biochemical studies showed decrease of fatty aldehyde dehydrogenase activity. Our results reinforce the distinct clinical, radiological, and biochemical features of ALDH3A2-related SLS which are the clue for targeted molecular testing. Moreover, we present additional unreported clinical findings and a novel mutation thus expanding the phenotypic and mutational spectrum of this rare disorder.

Phenotypic and mutational spectrum of thirty-five patients with Sjögren-Larsson syndrome: identification of eleven novel ALDH3A2 mutations and founder effects.

Sjögren-Larsson syndrome (SLS) is a rare neurocutaneous disorder characterized by congenital ichthyosis, spastic diplegia and intellectual disability. It is an inborn error of lipid metabolism caused by biallelic mutations in the ALDH3A2 gene encoding the fatty aldehyde dehydrogenase that plays a pivotal role in metabolism of long-chain aliphatic aldehydes and alcohols. In this report, we describe the clinical, neuro-radiological and molecular findings of 35 patients with SLS. All patients shared the typical clinical manifestations of SLS including spasticity, ichthyosis and intellectual disability. Brain MRI demonstrated deep while matter affection in all patients that varied in severity. Mutational analysis of the ALDH3A2 gene revealed 16 distinct mutations including 11 previously unreported ones. Three mutations (p.S365L, p.R9* and p.G400R) were recurrent in our patients with frequencies ranging from 12 to 24%. Interestingly, patients carrying the two new mutations p.R9* and p.G400R shared similar haplotypes suggesting possible founder effects in our population. In conclusion, we present a large cohort of patients from the same ethnicity with the characteristic clinical and brain imaging findings of SLS but with variable inter and intra familial severity and expressivity. We also identified many novel and founder ALDH3A2 mutations thus expanding the mutational spectrum of the disorder.

Congenital protein losing enteropathy: an inborn error of lipid metabolism due to DGAT1 mutations.

Protein-losing enteropathy (PLE) is a clinical disorder of protein loss from the gastrointestinal system that results in hypoproteinemia and malnutrition. This condition is associated with a wide range of gastrointestinal disorders. Recently, a unique syndrome of congenital PLE associated with biallelic mutations in the DGAT1 gene has been reported in a single family. We hypothesize that mutations in this gene are responsible for undiagnosed cases of PLE in infancy. Here we investigated three children in two families presenting with severe diarrhea, hypoalbuminemia and PLE, using clinical studies, homozygosity mapping, and exome sequencing. In one family, homozygosity mapping using SNP arrays revealed the DGAT1 gene as the best candidate gene for the proband. Sequencing of all the exons including flanking regions and promoter regions of the gene identified a novel homozygous missense variant, p.(Leu295Pro), in the highly conserved membrane-bound O-acyl transferase (MBOAT) domain of the DGAT1 protein. Expression studies verified reduced amounts of DGAT1 in patient fibroblasts. In a second family, exome sequencing identified a previously reported splice site mutation in intron 8. These cases of DGAT1 deficiency extend the molecular and phenotypic spectrum of PLE, suggesting a re-evaluation of the use of DGAT1 inhibitors for metabolic disorders including obesity and diabetes.

Implementation of Ketogenic Diet Therapy in Refractory Epilepsies

The Ketogenic Diet (KD) has been used in treatment of epilepsy in mainland China since 2004. Clinical indications of KD include: Glucose Transporter Type 1 (GLUT-1) deficiency, Pyruvate Dehydrogenase Deficiency (PDHD, myoclonus-astatic epilepsy (Doose syndrome), tuberous sclerosis complicated with or without epilepsy, Rett syndrome, Dravet syndrome, infantile spasms, and Landau-Kleffner syndrome, Lafora disease, and super-refractory status epilepticus. The contraindications of KD include: Inborn error of lipid metabolism, porphyria, and patients who are unable to cooperate with the KD. There should be standardized clinical consultation and evaluation before starting KD treatment; and special attention should be paid to selection and preparation of food, and to indication of age and geographic area etc. During the KD treatment, the transition time from ordinary diet to KD often takes 1-2 weeks; and a final 2: 1-4: 1 ketogenic diet ratio will normally produce ketosis of clinical therapeutic effect. The KD could be combined with anticonvulsant treatment. A qualified ketogenic diet therapy means: (1) Proper nutrition and growth with normal nutrition biomarkers; (2) Tasty foods: patients are willing to accept the therapeutic diet; (3) Ideal state of ketosis: urine ketone remains above (+++), blood ketone at about 4.0 mmol/L, blood sugar is controlled at 4.0 mmol/L, ratio of blood sugar/blood ketone is about 1: 1-2: 1; (4) Reasonable balanced food composition, defecate daily and naturally without constipation; (5) No remarkable complication(s). It is recommended that KD could be tried at least for three months continuously. Good responders should maintain the KD therapy for 2 yrs. or so. It often needs to take 3-6 months to return back to a regular diet. KD therapy should be monitored with close follow-ups and assessments. Our extensive experience has confirmed that it is safe in clinical practice.

The role of fatty aldehyde dehydrogenase in epidermal structure and function

The epidermal water barrier resides in the stratum corneum (SC) and is dependent on a highly organized network of multi-lamellar membranes comprised of a critical lipid composition. The SC membranes are formed from precursor membranes packaged in cytoplasmic lamellar bodies in the stratum granulosum and delivered to the SC by exocytosis. An abnormal lipid composition of the SC membranes often results in a disrupted water barrier and the clinical appearance of ichthyosis. This cutaneous feature is characteristic of Sjögren-Larsson syndrome (SLS), an inborn error of lipid metabolism caused by deficiency of fatty aldehyde dehydrogenase (FALDH). The contribution of FALDH to normal epidermal function has become increasingly evident with the recognition that this enzyme has an essential role in metabolism of several lipids, including fatty aldehydes and alcohols, ether glycerolipids, isoprenoid alcohols and certain lipids that undergo ω-oxidation, such as leukotriene B4 and very long-chain fatty acids. In the absence of FALDH, the skin produces lamellar bodies that are empty, lack their surrounding vesicle membranes or contain granular contents rather then the usual cargo membranes. These defective organelles also have impaired exocytosis, which results in structurally abnormal, deficient multi-lamellar membranes in the SC and a leaky water barrier. Although the exact biochemical mechanism for the cutaneous pathology is still unclear, studies in SLS demonstrate the critical importance of FALDH for normal epidermal structure and function.

Rhabdomyolysis in the Military: Recognizing Late-Onset Very Long-Chain Acyl Co-A Dehydrogenase Deficiency

Very long-chain acyl Co-A dehydrogenase deficiency, an inborn error of lipid metabolism, is commonly thought of as a disease of infancy or early childhood. However, several cases of late-onset very long-chain acyl Co-A dehydrogenase have been reported. This report of two military men who survived basic training before their disease presentation broadens the spectrum of late-onset disease, presents two previously unreported mutations, and demonstrates the fine line between athletic, active lifestyle and severe disease presentation.

Early Use of Drastic Therapy

Krabbe's disease, or globoid-cell leukodystrophy, is an inborn error of lipid metabolism first described in 1916 in two children with spasticity who died in infancy and were found to have “diffuse sclerosis” of the brain.1 Prominent features of the brain in affected children were decreased white-matter mass with relatively normal gray matter, generalized demyelination, and clusters of globoid cells in the white matter. Subsequent histopathological analyses have demonstrated that the changes in the white matter are due to the death of the myelin-forming oligodendrocytes in the central nervous system and Schwann cells in the peripheral nervous system, whereas the characteristic . . .

Farber's lipogranulomatosis: Report of a case and demonstration of an excess of free ceramide and ganglioside

The tenth case of Farber's lipogranulomatosis is reported. The clinical and pathologic features closely resemble those previously described except that in this patient the macula was also involved, there was nerve cell loss and neuronal storage in the cerebral cortex, and there was a strong family history of rheumatoid arthritis. The foam cells within the granulomas as well as certain of the neurons contained periodic acid-Schiff positive cytoplasmic material with the histochemical properties of an acidic glycolipid. Biochemical studies demonstrated an excess of gangliosides, roughly in proportion to the accumulation of the periodic acid-Schiff-positive material. The excess gangliosides were found to consist mainly of hematoside, the visceral ganglioside. Lymph nodes, liver, kidney and lung contained a ten- to sixtyfold excess of free ceramide, and similar very high levels of free ceramide were present in a subcutaneous nodule. In rats, subcutaneous injection of ceramide produced granulomas which resembled those found in the patients with the lipogranulomatosis syndrome. It is suggested that the lipogranulomatosis syndrome represents an inborn error of lipid metabolism. Its enzymatic basis is as yet undetermined.

Familial hypo-β-lipoproteinemia: A genetic disorder of lipid metabolism with nervous system involvement

A previously undescribed inborn error of lipid metabolism has been demonstrated in thirteen members of a kinship. The disorder was genetically transmitted in an autosomal dominant fashion. This abnormality, termed familial hypo-β-lipoproteinemia, consisted of a great reduction of serum β-lipoprotein content. Serum levels of cholesterol and phospholipid were low, whereas the concentrations of serum triglyceride were normal or low and that of α-lipoprotein normal. Vitamin E levels were decreased in five of the eleven persons so tested. Nine persons, all with serum cholesterol levels less than 100 mg. per 100 ml., showed acanthocytic red blood cells. These cells could be transformed to cells with normal forms by the in vitro addition of serum from hyperlipemic or hypercholesteremic persons. The clinical manifestations of this disorder are variable, and may be correlated with the severity of the biochemical abnormality. In its most severe form, as shown by the propositus, there is lack of responsiveness to local anesthetic agents, and signs and symptoms of a progressive demyelinating disorder affecting the central nervous system. Fasting peroral jejunal biopsy material from the propositus contained significant deposits of neutral fats beneath the lamina propria and in endothelial cells of capillaries containing lipid-laden mononuclear cells. The material presented suggests that hypo-β-lipoproteinemia may be an etiologic factor in some demyelinating disorders.

Infantile Niemann-Pick Disease

NIEMANN-Pick disease is an inborn error of lipid metabolism characterized by abnormal accumulation of sphingomyelin in various organs. Crocker¹divided the disease into the following four subgroups based on the combined clinical and chemical studies: classical infantile form (type A), visceral form (type B), subacute or juvenile form (type C), and Nova Scotian variant (type D). This classification seems to be generally accepted, but the well documented adult Neimann-Pick disease^2,3can be added as the fifth form. A recent investigation⁴indicated that the deficiency of sphingomyelinase, an enzyme which hydrolyzes sphingomyelin, is the basic enzymatic defect of Niemann-Pick disease. A more comprehensive study⁵of this enzyme revealed its deficiency only in the infantile and visceral forms. According to Crocker,¹the classical infantile form is the only one showing increased sphingomyelin in the brain. A characteristic pathological change of the central nervous system in infantile Niemann-Pick

1645. Refsum and α-oxidation: Stokke, O., Try, K. & Eldjarn, L. (1967), α-Oxidation as an alternative pathway for the degradation of branched-chain fatty acids in man, and its failure in patients with Refsum's disease. Biochim. Biophys. Acta144, 271

o1. Hereditary ataxic polyneuritis is a rare neurological disorder which wasclinically delineated by Refsum in 1946. The demonstration by Klenk and Kahlke in 1963 that patients with the disease accumulate large amounts of 3,7,-11,15-tetramethylhexadecanoic acid (phytanic acid) in various lipid fractions has triggered intense research activities in several laboratories.2. No endogenous synthesis of phytanic acid has been demonstrated. Thisacid stems from dietary preformed phytanic acid or phytol liberated from the chlorophyll molecule. The normal degradation of phytanic acid appears to be by a oxidation or by w oxidation followed by β oxidations. The inborn error of lipid metabolism which exists in Refsum's disease is a partial defect in the a oxidation mechanism.3. In two patients dietary restriction of phytol/phytanic acid intake hasresulted in a reduction to normal of phytanic acid in serum, in subcutaneous fat and probably also in other body stores. At the same time there was an improvement in nerve conductivity, a return of the CSF protein concentration to normal as well as a marked improvement in the general condition and well-being of the patients. No improvement was observed in the neurological defects.

Hereditary ataxic polyneuritis: Biochemical anddietary studies

o 1. Hereditary ataxic polyneuritis is a rare neurological disorder which wasclinically delineated by Refsum in 1946. The demonstration by Klenk and Kahlke in 1963 that patients with the disease accumulate large amounts of 3,7,-11,15-tetramethylhexadecanoic acid (phytanic acid) in various lipid fractions has triggered intense research activities in several laboratories. 2. No endogenous synthesis of phytanic acid has been demonstrated. Thisacid stems from dietary preformed phytanic acid or phytol liberated from the chlorophyll molecule. The normal degradation of phytanic acid appears to be by a oxidation or by w oxidation followed by β oxidations. The inborn error of lipid metabolism which exists in Refsum's disease is a partial defect in the a oxidation mechanism. 3. In two patients dietary restriction of phytol/phytanic acid intake hasresulted in a reduction to normal of phytanic acid in serum, in subcutaneous fat and probably also in other body stores. At the same time there was an improvement in nerve conductivity, a return of the CSF protein concentration to normal as well as a marked improvement in the general condition and well-being of the patients. No improvement was observed in the neurological defects.

Refsum's disease (heredopathia atactica polyneuritiformis): An inborn error of lipid metabolism with storage of 3,7,11,15-tetramethyl hexadecanoic acid: II. Isolation and identification of the storage product

A lipid extract of the urine and samples of liver, kidney, skeletal muscle and adipose tissue obtained by wedge biopsy from an eight year old girl suffering from Refsum's syndrome were analyzed for their lipid and fatty acid content. Total lipids were increased although the phospholipid fraction was decreased. An unusual fatty acid was detected in all samples by gas chromatography of the fatty acid methyl esters. In the liver, 72 per cent of all fatty acids of the cholesterol ester fraction consisted of the unusual fatty acid. By analytical methods the unusual compound was identified as 3,7,11,15-tetramethyl hexadecanoic acid. The isolated product was identical with authentic 3,7,11,15-tetramethyl hexadecanoic acid synthesized starting from phytol. The unusual fatty acid was also demonstrated in the serum of three other patients suffering from Refsum's syndrome. It was also detected in the serum of the mother of one patient. An examination of both parents of the original patient whose tissues were analyzed gave negative results.

ANOTHER CASE OF MALIGNANT HYPERLIPEMIA IN INFANCY?

To the Editor: In the March issue of theAmerican Journal of Diseases of Children(107:267, 1964), Hagberg et al, described two infants with malignant hyperlipemia thought to represent a previously unknown inborn error of lipid metabolism. When this article appeared it happened that we were seeing an infant with strikingly similar clinical features—perhaps a third example of such a disorder. A 4½-month-old white male infant was admitted March 3, 1964, after eight days of irregular fever. Prior to this illness he had been entirely well except for a very mild upper respiratory infection (URI) at age 2½ months. There is no family history of blood dyscrasia or metabolic disorder. On admission the infant did not appear ill (temperature, 105 F [40.6 C], pulse, 120; respiration, 24). Conspicuous hepatosplenomegaly was the only abnormal physical finding. Admission laboratory routines promptly revealed a disturbing pancytopenia (hemoglobin, 6.9 gm%; WBC 3,700/cu mm with

IDIOPATHIC HYPERLIPEMIA AND ISCHEMIC HEART DISEASE

Excerpt Idiopathic hyperlipemia is an inborn error of lipid metabolism characterized by elevated levels of serum triglyceride, cholesterol, and phospholipid. The elevated serum triglyceride level i...

AN INBORN ERROR OF LIPID METABOLISM

The present report concerns a new clinical syndrome characterized by hepatomeggaly, retardation of physical and mental growth, and a disturbance of lipids in the plasma. The abnormalities are present in two siblings born of parents who are second cousins. As far as can be determined, none of the six other siblings is affected. The disturbance of lipids is characterized by an increase in the concentrations of triglycerides and phospholipids in the plasma with relatively little increase in the concentration of total cholesterol. By means of paper and agar gel electrophoresis, the disturbance has been found to involve primarily an increase in the concentration of alpha2-lipoproteins. Using zone electrophoresis on starch medium, we have shown that there is an increase in concentration of phospholipids and triglycerides in the alpha2-lipoproteins and of triglycerides in the alpha1-lipoproteins. Analytic ultracentrifugation revealed an increase in each of the fractions, but was most marked in the lipoproteins with Sf 20-400. It would appear that this represents a new third "inborn error of lipid metabolism" in man.