Infantile Refsum Disease and its Treatment

Rajesh Kumar D.¹*, Manipriya L.², Radhika M.², Anusha S.²

¹Department of Pharmacology, Siddhartha Institute of Pharmaceutical Sciences, Narsaraopet, Guntur (Dt), Andhrapradesh.

²III Year B. Pharm Students, Siddhartha Institute of Pharmaceutical Sciences, Narsaraopet, Guntur (Dt), Andhrapradesh

ABSTRACT:

Infantile Refsum disease (IRD) also called infantile phytanic acid storage disease is a rare autosomal recessive congenital peroxisomal biogenesis disorder(PBD) .First it was discovered by Norwegian neurologist, Sigvald Refsum. Refsum disease also has a Latin name, heredopathia atactica polyneuritiformis, meaning a hereditary disease affecting balance and the peripheral nerves. There are four types of PBDs - Zellweger syndrome (ZS), neonatal adrenoleukodystrophy (NALD), infantile Refsum disease (IRD) and rhizomelic chondrodysplasia punctata (RCDP).Mainly it occurs due to elevated plasma concentration of phytanic acid. Blood levels of phytanic acid are increased in patients with Refsum disease. These levels are 10-50 mg/dL, whereas normal values are less than or equal to 0.2 mg/dL. Some of the causes of this disease are muscle conditions,brain conditions,genetic variations. The main symptoms are Visual impairments,Retinitis pigmentosa

and hearing impairments. IRD is definitively confirmed with biochemical evaluation. Diagnosis of IRD before birth is possible by genetic testing. the main differential diagnoses include Usher syndrome I and II.The main complication of this disease is Cardiac involvement i.e.produce conduction abnormalities and cardiomyopathy has been associated with premature death.Mainly it is treated by dietary restriction. Another common approach is in supplementing the child's diet with docosahexaenoic acid (DHA).

KEYWORDS: Infantile Refsum disease, Zellweger syndrome, Phytanic acid, Retinitis pigmentosa and cardiomyopathy.

DEFINITION:

Infantile Refsum disease (IRD) is a medical condition within the Zellweger spectrum of perixisome biogenesis disorders (PBDs), inherited genetic disorders that damage the white matter of the brain and affect motor movements. PBDs are part of a larger group of disorders called the leukodystrophies.^[1]

HISTORY:

In 1946 the disease was described by Norwegian neurologist, Sigvald Refsum. Refsum disease also has a Latin name, heredopathia atactica polyneuritiformis, meaning a hereditary disease affecting balance and the peripheral nerves. An American, Jan Cammermeyer, was the first to describe how the disease was caused by a defect in the process by which fatty acids are broken down.As first shown by Klenk and Kahlke in 1963, Refsum disease is associated with the accumulation of an unusual 20-carbon, branched-chain fatty acid called phytanic acid (3,7,11,15-tetramethylhexadecanoic acid) in blood and tissues^[9]. These findings identified Refsum disease as an inborn error of lipid metabolism inherited as an autosomal recessive trait.

INTRODUCTION:

There are four PBDs - Zellweger syndrome (ZS), neonatal adrenoleukodystrophy (NALD), infantile Refsum disease (IRD) and rhizomelic chondrodysplasia punctata (RCDP). The first three are really a single spectrum of disease, genetically and chemically almost indistinguishable and particular diagnosis is as much as anything based on the degree of severity of the child's condition. ZS is the most severe form, IRD the least, with NALD in the middle. These three diseases are known as the Zellweger spectrum, and affected children share a common set of abnormalities and disabilities. There is a great deal of clinical overlap between them, with no hard and fast lines.The Zellweger spectrum of PBDs include related, but not more severe, disorders referred to as Zellweger syndrome (ZS) and neonatal adrenoleukodystrophy. Collectively, these disorders are caused by inherited defects in any one of 12 genes, called PEX genes, which are required for the normal formation and function of peroxisomes. Peroxisomes are cell structures required for the normal formation and function of the brain, eyes, liver, kidneys, and bone^[2]. They contain enzymes that break down toxic substances in the cells, including very long chain fatty acids and phytanic acid (a type of fat found in certain foods), and synthesize certain fatty materials (lipids) that are required for cell function. When peroxisomes are not functioning, there is over-accumulation of very long chain fatty acids and phytanic acid, and a lack of bile acids and plasmalogens-specialized lipids found in cell membranes and the myelin sheaths and encase and protect nerve fibers. IRD has some residual perixisome function, resulting in less severe disease than in Zellweger syndrome. ^[1]

BACKGROUND:

Refsum disease (RD) is a neurocutaneous syndrome that is characterized biochemically by the accumulation of phytanic acid in plasma and tissues. Patients with Refsum disease are unable to degrade phytanic acid because of a deficient activity of phytanoyl-CoA hydroxylase (PhyH), a peroxisomal enzyme catalyzing the first step of phytanic acid alpha-oxidation^[5]. Refsum disease can be classified as a peroxisome biogenesis disorder. This category is inherited as an autosomal recessive trait and is characterized by altered peroxisome assembly, resulting in multiple peroxisome enzyme deficiencies, complex developmental sequelae, and progressive disabilities.Infantile Refsum disease is a peroxisome biogenesis disorder^[6]. The symptoms evolve slowly and insidiously from childhood through adolescence and early adulthood.

PATHOPHYSIOLOGY:

It is an autosomal recessive disorder of peroxisomal biogenesis, leading to many biochemical abnormalities, including elevated plasma concentration of phytanic acid, pristanic acid, very long chain fatty acids, and C27 bile acids.It is a characterized by defective peroxisomal alpha-oxidation of phytanic acid^[3]. Consequently, this unusual, exogenous C20-branched-chain (3,7,11,15 tetramethylhexadecanoic acid) fatty acid accumulates in blood and tissues. It is almost exclusively of exogenous origin and is delivered mainly from dietary plant chlorophyll and to a lesser extent from animal sources. Blood levels of phytanic acid are increased in patients with Refsum disease[4]. These levels are 10-50 mg/dL, whereas normal values are less than or equal to 0.2 mg/dL, and account for 5-30% of serum lipids.Phytanic acid replaces other fatty acids, including such essential ones as linoleic and arachidonic acids, in lipid moieties of various tissues.This situation leads to an essential fatty acid deficiency, which is associated with the development of ichthyosis (A congenital, often hereditary skin disease marked by dry, thickened, scaly skin. Also called fishskin disease).^[12]

SYMPTOMS:

Symptoms associated with IRD arise at birth or very early infancy and affect many different organ systems and tissues resulting in severe disease.

The main signs and symptoms include,

· Visual impairments

· Retinitis pigmentosa

· Nystagmus (involuntary jerky eye movements)

· Hearing impairments

· Hypotonia (decreased muscle tone)

· Failure to thrive

· Developmental delay

· Ataxia (impaired muscle coordination)

· Hepatomegaly (enlargement of the liver)

· Hypocholesterolemia (abnormally low cholesterol)

· Mild facial abnormalities

· mental and growth disabilities

· white matter abnormalities of brain

· Early osteoporosis(decalcifications of the bone) ^[14]

CAUSES :

Some of the causes of IRD are,

· Leukodystrophy

· Muscle conditions

· Brain conditions

· Genetic Disease^[7]

OCCURRENCE:

By 1991 a total of 120 people with the disease had been identified, seven from Sweden and the others primarily from Norway, England, Ireland, Germany and France. It is likely that many cases remain undiagnosed. The condition is equally prevalent in men and women. In England it is estimated that one person in a million has the disease.

EPIDEMIOLOGY:

Prevalence of the disease is of 1 case per 1.000.000 and males and females are equally affected. ^[12]

Mortality/Morbidity:

In patients who are untreated or diagnosed late, severe neurological impairment, wasting, and depression develop, subsequently leading to a high mortality rate.

DIAGNOSIS:

IRD is diagnosed though a combination of consistent medical history, physical exam findings, and laboratory and genetic testing.IRD is definitively confirmed with biochemical evaluation. Plasma very-long-chain fatty acid (VLCFA) levels indicate defects in peroxisomal fatty acid metabolism with elevated plasma concentrations of C26:0 and C26:1 and elevated ratios of C24/C22 and C26/C22. Erythrocyte membrane concentrations of plasmalogens C16 and C18 are usually reduced, but can be normal. Plasma pipecolic acid levels and bile acid intermediates (THCH and DHCA) are increased. Occasionally, VLCFA levels and enzymatic assays in fibroblasts can be within the normal range, requiring additional assessment in expert laboratories. Sequence analysis of the 13 PEX genes can be performed. MRI can be used to identify myelin changes^.[8]

Typically, parents bring newborns to their physicians because of the signs of low muscle tone. Other times, the characteristic facial abnormalities or a failure to grow at appropriate rates is noted. These findings raise suspicion for a genetic syndrome or metabolic disorder, and further tests are conducted.

The main differential diagnoses include Usher syndrome I and II. ^[17]

· Usher syndrome type I is characterized by a congenital, bilateral, profound sensorineural hearing loss, vestibular areflexia, and adolescent-onset retinitis pigmentosa. Inheritance is autosomal recessive