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Sialic acid storage disease, severe infantile type(ISSD)

MedGen UID:
203367
Concept ID:
C1096902
Disease or Syndrome
Synonyms: Free sialic acid storage disease, infantile form; Infantile Free Sialic Acid Storage Disease; Infantile Sialic Acid Storage Disease; Infantile sialic acid storage disorder; ISSD; N-Acetylneuraminic acid storage disease; NANA STORAGE DISEASE; Sialuria, infantile form
SNOMED CT: Infantile sialic acid storage disease (34566007); Sialic acid storage disease, severe infantile type (34566007); Sialuria, infantile type (34566007)
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).
 
Gene (location): SLC17A5 (6q13)
 
Monarch Initiative: MONDO:0010027
OMIM®: 269920
Orphanet: ORPHA309324

Disease characteristics

Excerpted from the GeneReview: Free Sialic Acid Storage Disorders
Free sialic acid storage disorders (FSASDs) are a spectrum of neurodegenerative disorders resulting from increased lysosomal storage of free sialic acid. Historically, FSASD was divided into separate allelic disorders: Salla disease, intermediate severe Salla disease, and infantile free sialic acid storage disease (ISSD). The mildest type was Salla disease, characterized by normal appearance and absence of neurologic findings at birth, followed by slowly progressive neurologic deterioration resulting in mild-to-moderate psychomotor delays, spasticity, athetosis, and epileptic seizures. Salla disease was named for a municipality in Finnish Lapland where a specific founder variant is relatively prevalent. However, the term Salla has been used in the literature to refer to less severe FSASD. More severe FSASD is historically referred to as ISSD, and is characterized by severe developmental delay, coarse facial features, hepatosplenomegaly, and cardiomegaly; death usually occurs in early childhood. [from GeneReviews]
Authors:
David Adams  |  Melissa Wasserstein   view full author information

Additional descriptions

From OMIM
Sialic acid storage diseases are autosomal recessive neurodegenerative disorders that may present as a severe infantile form (ISSD) or as a slowly progressive adult form that is prevalent in Finland (Salla disease). The main symptoms are hypotonia, cerebellar ataxia, and mental retardation; visceromegaly and coarse features are also present in the infantile cases. Progressive cerebellar atrophy and dysmyelination have been documented by MRI. Enlarged lysosomes are seen on electron microscopic studies, and patients excrete large amounts of free sialic acid in the urine (Verheijen et al., 1999).  http://www.omim.org/entry/269920
From MedlinePlus Genetics
Sialic acid storage disease is an inherited disorder that primarily affects the nervous system. People with sialic acid storage disease have signs and symptoms that may vary widely in severity. This disorder is generally classified into one of three forms: infantile free sialic acid storage disease, Salla disease, and intermediate severe Salla disease.

Infantile free sialic acid storage disease (ISSD) is the most severe form of this disorder. Babies with this condition have severe developmental delay, weak muscle tone (hypotonia), and failure to gain weight and grow at the expected rate (failure to thrive). They may have unusual facial features that are often described as "coarse," seizures, bone malformations, an enlarged liver and spleen (hepatosplenomegaly), and an enlarged heart (cardiomegaly). The abdomen may be swollen due to the enlarged organs and an abnormal buildup of fluid in the abdominal cavity (ascites). Affected infants may have a condition called hydrops fetalis in which excess fluid accumulates in the body before birth. Children with this severe form of the condition usually live only into early childhood.

People with intermediate severe Salla disease have signs and symptoms that fall between those of ISSD and Salla disease in severity.

Salla disease is a less severe form of sialic acid storage disease. Babies with Salla disease usually begin exhibiting hypotonia during the first year of life and go on to experience progressive neurological problems. Signs and symptoms of Salla disease include intellectual disability and developmental delay, seizures, problems with movement and balance (ataxia), abnormal tensing of the muscles (spasticity), and involuntary slow, sinuous movements of the limbs (athetosis). Individuals with Salla disease usually survive into adulthood.  https://medlineplus.gov/genetics/condition/sialic-acid-storage-disease

Clinical features

From HPO
Nephrotic syndrome
MedGen UID:
10308
Concept ID:
C0027726
Disease or Syndrome
Nephrotic syndrome is a collection of findings resulting from glomerular dysfunction with an increase in glomerular capillary wall permeability associated with pronounced proteinuria. Nephrotic syndrome refers to the constellation of clinical findings that result from severe renal loss of protein, with Proteinuria and hypoalbuminemia, edema, and hyperlipidemia.
Abnormal foot morphology
MedGen UID:
1762829
Concept ID:
C5399834
Anatomical Abnormality
An abnormality of the skeleton of foot.
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.
Failure to thrive
MedGen UID:
746019
Concept ID:
C2315100
Disease or Syndrome
Failure to thrive (FTT) refers to a child whose physical growth is substantially below the norm.
Ascites
MedGen UID:
416
Concept ID:
C0003962
Disease or Syndrome
Accumulation of fluid in the peritoneal cavity.
Hepatomegaly
MedGen UID:
42428
Concept ID:
C0019209
Finding
Abnormally increased size of the liver.
Hydrocephalus
MedGen UID:
9335
Concept ID:
C0020255
Disease or Syndrome
Hydrocephalus is an active distension of the ventricular system of the brain resulting from inadequate passage of CSF from its point of production within the cerebral ventricles to its point of absorption into the systemic circulation.
Seizure
MedGen UID:
20693
Concept ID:
C0036572
Sign or Symptom
A seizure is an intermittent abnormality of nervous system physiology characterized by a transient occurrence of signs and/or symptoms due to abnormal excessive or synchronous neuronal activity in the brain.
Cerebral atrophy
MedGen UID:
116012
Concept ID:
C0235946
Disease or Syndrome
Atrophy (wasting, decrease in size of cells or tissue) affecting the cerebrum.
Global developmental delay
MedGen UID:
107838
Concept ID:
C0557874
Finding
A delay in the achievement of motor or mental milestones in the domains of development of a child, including motor skills, speech and language, cognitive skills, and social and emotional skills. This term should only be used to describe children younger than five years of age.
Hypotonia
MedGen UID:
10133
Concept ID:
C0026827
Finding
Hypotonia is an abnormally low muscle tone (the amount of tension or resistance to movement in a muscle). Even when relaxed, muscles have a continuous and passive partial contraction which provides some resistance to passive stretching. Hypotonia thus manifests as diminished resistance to passive stretching. Hypotonia is not the same as muscle weakness, although the two conditions can co-exist.
Osteopenia
MedGen UID:
18222
Concept ID:
C0029453
Disease or Syndrome
Osteopenia is a term to define bone density that is not normal but also not as low as osteoporosis. By definition from the World Health Organization osteopenia is defined by bone densitometry as a T score -1 to -2.5.
Metaphyseal irregularity
MedGen UID:
325478
Concept ID:
C1838662
Finding
Irregularity of the normally smooth surface of the metaphyses.
J-shaped sella turcica
MedGen UID:
381480
Concept ID:
C1854718
Finding
A deformity of the sella turcica whereby the sella extends further anterior than normal such that the anterior clinoid process appears to overhang it, giving the appearance of the letter J on imaging of the skull.
Generalized hypotonia
MedGen UID:
346841
Concept ID:
C1858120
Finding
Generalized muscular hypotonia (abnormally low muscle tone).
Abnormal thorax morphology
MedGen UID:
867424
Concept ID:
C4021797
Anatomical Abnormality
Any abnormality of the thorax (the region of the body formed by the sternum, the thoracic vertebrae and the ribs).
Splenomegaly
MedGen UID:
52469
Concept ID:
C0038002
Finding
Abnormal increased size of the spleen.
Vacuolated lymphocytes
MedGen UID:
332307
Concept ID:
C1836855
Finding
The presence of clear, sharply defined vacuoles in the lymphocyte cytoplasm.
Conjugated hyperbilirubinemia
MedGen UID:
82787
Concept ID:
C0268307
Disease or Syndrome
Abnormally high level of conjugated bilirubin in the blood.
High palate
MedGen UID:
66814
Concept ID:
C0240635
Congenital Abnormality
Height of the palate more than 2 SD above the mean (objective) or palatal height at the level of the first permanent molar more than twice the height of the teeth (subjective).
Gingival overgrowth
MedGen UID:
87712
Concept ID:
C0376480
Finding
Hyperplasia of the gingiva (that is, a thickening of the soft tissue overlying the alveolar ridge. The degree of thickening ranges from involvement of the interdental papillae alone to gingival overgrowth covering the entire tooth crown.
Epicanthus
MedGen UID:
151862
Concept ID:
C0678230
Congenital Abnormality
Epicanthus is a condition in which a fold of skin stretches from the upper to the lower eyelid, partially covering the inner canthus. Usher (1935) noted that epicanthus is a normal finding in the fetus of all races. Epicanthus also occurs in association with hereditary ptosis (110100).
Anteverted nares
MedGen UID:
326648
Concept ID:
C1840077
Finding
Anteriorly-facing nostrils viewed with the head in the Frankfurt horizontal and the eyes of the observer level with the eyes of the subject. This gives the appearance of an upturned nose (upturned nasal tip).
Coarse facial features
MedGen UID:
335284
Concept ID:
C1845847
Finding
Absence of fine and sharp appearance of brows, nose, lips, mouth, and chin, usually because of rounded and heavy features or thickened skin with or without thickening of subcutaneous and bony tissues.
Hypopigmentation of the skin
MedGen UID:
102477
Concept ID:
C0162835
Disease or Syndrome
A reduction of skin color related to a decrease in melanin production and deposition.
Fair hair
MedGen UID:
336542
Concept ID:
C1849221
Finding
A lesser degree of hair pigmentation than would otherwise be expected.
Hydrops fetalis
MedGen UID:
6947
Concept ID:
C0020305
Disease or Syndrome
The abnormal accumulation of fluid in two or more fetal compartments, including ascites, pleural effusion, pericardial effusion, and skin edema.
Premature birth
MedGen UID:
57721
Concept ID:
C0151526
Pathologic Function
The birth of a baby of less than 37 weeks of gestational age.
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).
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.

Term Hierarchy

CClinical test,  RResearch test,  OOMIM,  GGeneReviews,  VClinVar  

Professional guidelines

PubMed

Taconet S, Dreux S, Guimiot F, Pettazzoni M, Allaf B, Spaggiari E, Rosenblatt J, Khung-Savatovsky S
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Aula N, Aula P
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Recent clinical studies

Etiology

Huizing M, Hackbarth ME, Adams DR, Wasserstein M, Patterson MC, Walkley SU, Gahl WA; FSASD Consortium
Neurosci Lett 2021 Jun 11;755:135896. Epub 2021 Apr 20 doi: 10.1016/j.neulet.2021.135896. PMID: 33862140Free PMC Article
Huizing M, Gahl WA
Biochim Biophys Acta Biomembr 2020 Dec 1;1862(12):183336. Epub 2020 May 8 doi: 10.1016/j.bbamem.2020.183336. PMID: 32389669Free PMC Article
Ruivo R, Anne C, Sagné C, Gasnier B
Biochim Biophys Acta 2009 Apr;1793(4):636-49. Epub 2008 Dec 24 doi: 10.1016/j.bbamcr.2008.12.008. PMID: 19146888
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Cantz M, Ulrich-Bott B
J Inherit Metab Dis 1990;13(4):523-37. doi: 10.1007/BF01799510. PMID: 2122119

Diagnosis

Aulanko I, Rahikkala E, Moilanen J
Eur Child Adolesc Psychiatry 2023 Oct;32(10):2043-2047. Epub 2022 Jul 7 doi: 10.1007/s00787-022-02031-5. PMID: 35796883Free PMC Article
Huizing M, Hackbarth ME, Adams DR, Wasserstein M, Patterson MC, Walkley SU, Gahl WA; FSASD Consortium
Neurosci Lett 2021 Jun 11;755:135896. Epub 2021 Apr 20 doi: 10.1016/j.neulet.2021.135896. PMID: 33862140Free PMC Article
Huizing M, Gahl WA
Biochim Biophys Acta Biomembr 2020 Dec 1;1862(12):183336. Epub 2020 May 8 doi: 10.1016/j.bbamem.2020.183336. PMID: 32389669Free PMC Article
Renaud DL
Semin Neurol 2012 Feb;32(1):51-4. Epub 2012 Mar 15 doi: 10.1055/s-0032-1306386. PMID: 22422206
Sperl W, Gruber W, Quatacker J, Monnens L, Thoenes W, Fink FM, Paschke E
Eur J Pediatr 1990 Apr;149(7):477-82. doi: 10.1007/BF01959399. PMID: 2347341

Therapy

Aulanko I, Rahikkala E, Moilanen J
Eur Child Adolesc Psychiatry 2023 Oct;32(10):2043-2047. Epub 2022 Jul 7 doi: 10.1007/s00787-022-02031-5. PMID: 35796883Free PMC Article
Pluvinage JV, Sun J, Claes C, Flynn RA, Haney MS, Iram T, Meng X, Lindemann R, Riley NM, Danhash E, Chadarevian JP, Tapp E, Gate D, Kondapavulur S, Cobos I, Chetty S, Pașca AM, Pașca SP, Berry-Kravis E, Bertozzi CR, Blurton-Jones M, Wyss-Coray T
Sci Transl Med 2021 Dec;13(622):eabg2919. Epub 2021 Dec 1 doi: 10.1126/scitranslmed.abg2919. PMID: 34851695Free PMC Article
Cadaoas J, Boyle G, Jungles S, Cullen S, Vellard M, Grubb JH, Jurecka A, Sly W, Kakkis E
Mol Genet Metab 2020 May;130(1):65-76. Epub 2020 Mar 6 doi: 10.1016/j.ymgme.2020.02.009. PMID: 32192868
Wen XY, Tarailo-Graovac M, Brand-Arzamendi K, Willems A, Rakic B, Huijben K, Da Silva A, Pan X, El-Rass S, Ng R, Selby K, Philip AM, Yun J, Ye XC, Ross CJ, Lehman AM, Zijlstra F, Abu Bakar N, Drögemöller B, Moreland J, Wasserman WW, Vallance H, van Scherpenzeel M, Karbassi F, Hoskings M, Engelke U, de Brouwer A, Wevers RA, Pshezhetsky AV, van Karnebeek CD, Lefeber DJ
JCI Insight 2018 Dec 20;3(24) doi: 10.1172/jci.insight.122373. PMID: 30568043Free PMC Article
Boomkamp SD, Butters TD
Subcell Biochem 2008;49:441-67. doi: 10.1007/978-1-4020-8831-5_17. PMID: 18751922

Prognosis

Chapleau A, Mirchi A, Tran LT, Poulin C, Bernard G
Pediatr Neurol 2023 Nov;148:133-137. Epub 2023 Aug 19 doi: 10.1016/j.pediatrneurol.2023.08.013. PMID: 37713976
Zielonka M, Garbade SF, Kölker S, Hoffmann GF, Ries M
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Stevenson RE, Lubinsky M, Taylor HA, Wenger DA, Schroer RJ, Olmstead PM
Pediatrics 1983 Oct;72(4):441-9. PMID: 6889058

Clinical prediction guides

Chapleau A, Mirchi A, Tran LT, Poulin C, Bernard G
Pediatr Neurol 2023 Nov;148:133-137. Epub 2023 Aug 19 doi: 10.1016/j.pediatrneurol.2023.08.013. PMID: 37713976
Verheijen FW, Verbeek E, Aula N, Beerens CE, Havelaar AC, Joosse M, Peltonen L, Aula P, Galjaard H, van der Spek PJ, Mancini GM
Nat Genet 1999 Dec;23(4):462-5. doi: 10.1038/70585. PMID: 10581036
Mancini GM, Verheijen FW, Beerens CE, Renlund M, Aula P
Dev Neurosci 1991;13(4-5):327-30. doi: 10.1159/000112181. PMID: 1817039
Sperl W, Gruber W, Quatacker J, Monnens L, Thoenes W, Fink FM, Paschke E
Eur J Pediatr 1990 Apr;149(7):477-82. doi: 10.1007/BF01959399. PMID: 2347341
Paschke E, Trinkl G, Erwa W, Pavelka M, Mutz I, Roscher A
Clin Genet 1986 May;29(5):417-24. doi: 10.1111/j.1399-0004.1986.tb00514.x. PMID: 3742847

Recent systematic reviews

Iyer NS, Gimovsky AC, Ferreira CR, Critchlow E, Al-Kouatly HB
Clin Genet 2021 Nov;100(5):493-503. Epub 2021 Jul 16 doi: 10.1111/cge.14005. PMID: 34057202

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