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Phytanic acid storage disease(HMSN4)

MedGen UID:
11161
Concept ID:
C0034960
Disease or Syndrome
Synonyms: Disorder of cornification 11 (phytanic acid type); Doc 11 (phytanic acid type); Herditary sensory and motor neuropathy type 4; Heredopathia atactica polyneuritiformis; HMSN 4; HMSN IV; Hypertrophic neuropathy of Refsum; PEX7-Related Refsum Disease; PHYH-Related Refsum Disease; Phytanic acid oxidase deficiency; Refsum Disease; REFSUM DISEASE, CLASSIC
SNOMED CT: Hereditary motor and sensory neuropathy type IV (25362006); Heredoataxic atactica polyneuritiformis (25362006); Heredoataxic hemeralopica polyneuritiformis (25362006); Hereditary motor and sensory neuropathy, type IV (25362006); HSMN IV (25362006); Phytanic acid storage disease (25362006); Refsum's disease (25362006); Heredopathia atactica polyneuritiformis (25362006); Refsum syndrome (25362006); Heredoataxia hemeralopica polyneuritiformis (25362006); Refsum-Thiébaut disease (25362006); Hereditary sensory-motor neuropathy, type IV (25362006); Refsum-Thiebaut disease (25362006)
Modes of inheritance:
Autosomal recessive inheritance
MedGen UID:
141025
Concept ID:
C0441748
Intellectual Product
Source: Orphanet
A mode of inheritance that is observed for traits related to a gene encoded on one of the autosomes (i.e., the human chromosomes 1-22) in which a trait manifests in individuals with two pathogenic alleles, either homozygotes (two copies of the same mutant allele) or compound heterozygotes (whereby each copy of a gene has a distinct mutant allele).
 
Genes (locations): PEX7 (6q23.3); PHYH (10p13)
 
Monarch Initiative: MONDO:0009958
OMIM®: 266500
Orphanet: ORPHA773

Disease characteristics

Excerpted from the GeneReview: Adult Refsum Disease
Adult Refsum disease (ARD is associated with elevated plasma phytanic acid levels, late childhood-onset (or later) retinitis pigmentosa, and variable combinations of anosmia, polyneuropathy, deafness, ataxia, and ichthyosis. Onset of symptoms ranges from age seven months to older than age 50 years. Cardiac arrhythmia and heart failure caused by cardiomyopathy are potentially severe health problems that develop later in life. [from GeneReviews]
Authors:
Hans R Waterham  |  Ronald JA Wanders  |  Bart P Leroy   view full author information

Additional descriptions

From OMIM
Refsum disease is an autosomal recessive inborn error of lipid metabolism classically characterized by a tetrad of clinical abnormalities: retinitis pigmentosa, peripheral neuropathy, cerebellar ataxia, and elevated protein levels in the cerebrospinal fluid (CSF) without an increase in the number of cells. However, not all patients show all these features. All patients have accumulation of an unusual branched-chain fatty acid, phytanic acid, in blood and tissues. Other variable features include cardiac dysfunction, nerve deafness, ichthyosis, and multiple epiphyseal dysplasia (review by Skjeldal et al., 1987). Increased levels of phytanic acid can also be found in peroxisomal biogenesis disorders; see Zellweger syndrome (see 214100) (Skjeldal et al., 1987). Infantile Refsum disease (see PBD1B, 601539) is a distinct disorder with a different phenotype and genetic basis. A phenotype clinically indistinguishable from that of classic Refsum disease (PBD9B; 614879), but with a different biochemical profile, can be caused by mutation in the gene encoding peroxin-7 (PEX7; 601757) on chromosome 6q.  http://www.omim.org/entry/266500
From MedlinePlus Genetics
Refsum disease is an inherited condition that causes vision loss, absence of the sense of smell (anosmia), and a variety of other signs and symptoms.

The vision loss associated with Refsum disease is caused by an eye disorder called retinitis pigmentosa. This disorder affects the retina, the light-sensitive layer at the back of the eye. Vision loss occurs as the light-sensing cells of the retina gradually deteriorate. The first sign of retinitis pigmentosa is usually a loss of night vision, which often becomes apparent in childhood. Over a period of years, the disease disrupts side (peripheral) vision and may eventually lead to blindness.

Vision loss and anosmia are seen in almost everyone with Refsum disease, but other signs and symptoms vary. About one-third of affected individuals are born with bone abnormalities of the hands and feet. Features that appear later in life can include progressive muscle weakness and wasting; poor balance and coordination (ataxia); hearing loss; and dry, scaly skin (ichthyosis). Additionally, some people with Refsum disease develop an abnormal heart rhythm (arrhythmia) and related heart problems that can be life-threatening.  https://medlineplus.gov/genetics/condition/refsum-disease

Clinical features

From HPO
Abnormal renal physiology
MedGen UID:
508816
Concept ID:
C0151746
Pathologic Function
An abnormal functionality of the kidney.
Limb muscle weakness
MedGen UID:
107956
Concept ID:
C0587246
Finding
Reduced strength and weakness of the muscles of the arms and legs.
Pes cavus
MedGen UID:
675590
Concept ID:
C0728829
Congenital Abnormality
An increase in height of the medial longitudinal arch of the foot that does not flatten on weight bearing (i.e., a distinctly hollow form of the sole of the foot when it is bearing weight).
Short fourth metatarsal
MedGen UID:
336358
Concept ID:
C1848514
Finding
Short fourth metatarsal bone.
Cardiac arrhythmia
MedGen UID:
2039
Concept ID:
C0003811
Finding
Any cardiac rhythm other than the normal sinus rhythm. Such a rhythm may be either of sinus or ectopic origin and either regular or irregular. An arrhythmia may be due to a disturbance in impulse formation or conduction or both.
Cardiomegaly
MedGen UID:
5459
Concept ID:
C0018800
Finding
Increased size of the heart, clinically defined as an increased transverse diameter of the cardiac silhouette that is greater than or equal to 50% of the transverse diameter of the chest (increased cardiothoracic ratio) on a posterior-anterior projection of a chest radiograph or a computed tomography.
Congestive heart failure
MedGen UID:
9169
Concept ID:
C0018802
Disease or Syndrome
The presence of an abnormality of cardiac function that is responsible for the failure of the heart to pump blood at a rate that is commensurate with the needs of the tissues or a state in which abnormally elevated filling pressures are required for the heart to do so. Heart failure is frequently related to a defect in myocardial contraction.
Cardiomyopathy
MedGen UID:
209232
Concept ID:
C0878544
Disease or Syndrome
A myocardial disorder in which the heart muscle is structurally and functionally abnormal, in the absence of coronary artery disease, hypertension, valvular disease and congenital heart disease sufficient to cause the observed myocardial abnormality.
Sensorineural hearing loss disorder
MedGen UID:
9164
Concept ID:
C0018784
Disease or Syndrome
A type of hearing impairment in one or both ears related to an abnormal functionality of the cochlear nerve.
Anosmia
MedGen UID:
1950
Concept ID:
C0003126
Finding
An inability to perceive odors. This is a general term describing inability to smell arising in any part of the process of smelling from absorption of odorants into the nasal mucous overlying the olfactory epithelium, diffusion to the cilia, binding to olfactory receptor sites, generation of action potentials in olfactory neurons, and perception of a smell.
Cerebellar ataxia
MedGen UID:
849
Concept ID:
C0007758
Disease or Syndrome
Cerebellar ataxia refers to ataxia due to dysfunction of the cerebellum. This causes a variety of elementary neurological deficits including asynergy (lack of coordination between muscles, limbs and joints), dysmetria (lack of ability to judge distances that can lead to under- or overshoot in grasping movements), and dysdiadochokinesia (inability to perform rapid movements requiring antagonizing muscle groups to be switched on and off repeatedly).
Hyporeflexia
MedGen UID:
195967
Concept ID:
C0700078
Finding
Reduction of neurologic reflexes such as the knee-jerk reaction.
Sensorimotor neuropathy
MedGen UID:
207266
Concept ID:
C1112256
Disease or Syndrome
Increased CSF protein concentration
MedGen UID:
329971
Concept ID:
C1806780
Finding
Increased concentration of protein in the cerebrospinal fluid.
Somatic sensory dysfunction
MedGen UID:
1790456
Concept ID:
C5551413
Finding
An abnormality of the primary sensation that is mediated by peripheral nerves (pain, temperature, touch, vibration, joint position). The word hypoesthesia (or hypesthesia) refers to a reduction in cutaneous sensation to a specific type of testing.
Multiple epiphyseal dysplasia
MedGen UID:
6461
Concept ID:
C0026760
Congenital Abnormality
A rare group of primary bone dysplasia disorders characterized by the association of epiphyseal anomalies of long bones causing joint pain early in life, recurrent osteochondritis and early arthrosis. This group contains an heterogeneous group of diseases with variable expression. Common reported clinical signs include waddling gait and pain at onset, and moderate short stature. Some forms are mainly limited to the femoral epiphyses, while several other syndromes are characterized by the association of multiple epiphyseal dysplasia with other clinical manifestations such as myopia, deafness and facial dysmorphism. Diagnosis relies on identification of the radiological features.
Elevated circulating phytanic acid concentration
MedGen UID:
869360
Concept ID:
C4023786
Finding
An abnormal elevation of phytanic acid.
Reduced phytanic acid oxidase activity in cultured fibroblasts
MedGen UID:
1841996
Concept ID:
C5826893
Finding
Activity of the enzyme phytanoyl-CoA hydroxylase (PhyH; EC 1.14.11.18) below the lower limit of normal in cultured fibroblasts. PhyH plays a role in the catabolism of phytanic acid, a branched-chain fatty acid that is a normal constituent of the human diet.
Ichthyosis
MedGen UID:
7002
Concept ID:
C0020757
Disease or Syndrome
An abnormality of the skin characterized the presence of excessive amounts of dry surface scales on the skin resulting from an abnormality of keratinization.
Ptosis
MedGen UID:
2287
Concept ID:
C0005745
Disease or Syndrome
The upper eyelid margin is positioned 3 mm or more lower than usual and covers the superior portion of the iris (objective); or, the upper lid margin obscures at least part of the pupil (subjective).
Miosis
MedGen UID:
6409
Concept ID:
C0026205
Disease or Syndrome
Abnormal (non-physiological) constriction of the pupil.
Night blindness
MedGen UID:
10349
Concept ID:
C0028077
Disease or Syndrome
Inability to see well at night or in poor light.
Nystagmus
MedGen UID:
45166
Concept ID:
C0028738
Disease or Syndrome
Rhythmic, involuntary oscillations of one or both eyes related to abnormality in fixation, conjugate gaze, or vestibular mechanisms.
Retinal degeneration
MedGen UID:
48432
Concept ID:
C0035304
Finding
A nonspecific term denoting degeneration of the retinal pigment epithelium and/or retinal photoreceptor cells.
Cataract
MedGen UID:
39462
Concept ID:
C0086543
Disease or Syndrome
A cataract is an opacity or clouding that develops in the crystalline lens of the eye or in its capsule.
Rod-cone dystrophy
MedGen UID:
1632921
Concept ID:
C4551714
Disease or Syndrome
An inherited retinal disease subtype in which the rod photoreceptors appear to be more severely affected than the cone photoreceptors. Typical presentation is with nyctalopia (due to rod dysfunction) followed by loss of mid-peripheral field of vision, which gradually extends and leaves many patients with a small central island of vision due to the preservation of macular cones.

Term Hierarchy

CClinical test,  RResearch test,  OOMIM,  GGeneReviews,  VClinVar  
  • CROGVPhytanic acid storage disease
Follow this link to review classifications for Phytanic acid storage disease in Orphanet.

Professional guidelines

PubMed

Weinstein R
J Clin Apher 1999;14(4):181-4. doi: 10.1002/(sici)1098-1101(1999)14:4<181::aid-jca5>3.0.co;2-z. PMID: 10611628
Djupesland G, Flottorp G, Refsum S
Neurology 1983 Feb;33(2):237-40. doi: 10.1212/wnl.33.2.237. PMID: 6185882
Refsum S
Arch Neurol 1981 Oct;38(10):605-6. doi: 10.1001/archneur.1981.00510100033003. PMID: 6170281

Recent clinical studies

Etiology

Lindström K, Breimer ME, Jovall PA, Lanne B, Pimlott W, Samuelsson BE
J Biochem 1992 Mar;111(3):337-45. doi: 10.1093/oxfordjournals.jbchem.a123759. PMID: 1587795
Wanders RJ, Boltshauser E, Steinmann B, Spycher MA, Schutgens RB, van den Bosch H, Tager JM
J Neurol Sci 1990 Aug;98(1):1-11. doi: 10.1016/0022-510x(90)90177-o. PMID: 1700075

Diagnosis

Weinstein R
J Clin Apher 1999;14(4):181-4. doi: 10.1002/(sici)1098-1101(1999)14:4<181::aid-jca5>3.0.co;2-z. PMID: 10611628
Budden SS, Kennaway NG, Buist NR, Poulos A, Weleber RG
J Pediatr 1986 Jan;108(1):33-9. doi: 10.1016/s0022-3476(86)80765-x. PMID: 2418187
Weleber RG, Tongue AC, Kennaway NG, Budden SS, Buist NR
Arch Ophthalmol 1984 Sep;102(9):1317-21. doi: 10.1001/archopht.1984.01040031067026. PMID: 6206835
Scotto JM, Hadchouel M, Odievre M, Laudat MH, Saudubray JM, Dulac O, Beucler I, Beaune P
J Inherit Metab Dis 1982;5(2):83-90. doi: 10.1007/BF01799998. PMID: 6188882
Molzer B, Bernheimer H, Barolin GS, Höfinger E, Lenz H
Clin Chim Acta 1979 Jan 15;91(2):133-40. doi: 10.1016/0009-8981(79)90447-9. PMID: 83207

Therapy

Weinstein R
J Clin Apher 1999;14(4):181-4. doi: 10.1002/(sici)1098-1101(1999)14:4<181::aid-jca5>3.0.co;2-z. PMID: 10611628
Robertson EF, Poulos A, Sharp P, Manson J, Wise G, Jaunzems A, Carter R
Eur J Pediatr 1988 Feb;147(2):133-42. doi: 10.1007/BF00442210. PMID: 2452736
Djupesland G, Flottorp G, Refsum S
Neurology 1983 Feb;33(2):237-40. doi: 10.1212/wnl.33.2.237. PMID: 6185882

Clinical prediction guides

Scotto JM, Hadchouel M, Odievre M, Laudat MH, Saudubray JM, Dulac O, Beucler I, Beaune P
J Inherit Metab Dis 1982;5(2):83-90. doi: 10.1007/BF01799998. PMID: 6188882

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