neurodegeneration

Encephalopathy, Progressive, with Amyotrophy and Optic Atrophy

Clinical Characteristics
Ocular Features: 

Optic atrophy is present.

Systemic Features: 

This is a progressive neurodegenerative condition in which hypotonia and delayed development are evident between birth and 14 months of age.  Developmental milestones, if attained, soon regress accompanied by distal amyotrophy, cognitive impairment that may be severe, ataxia, spastic tetraplegia, dysarthria, and scoliosis.  Seizures often occur.

Brain imaging reveals cerebellar and cerebral atrophy.  Iron accumulation may be seen in the pallidum and substantia nigra.  The corpus callosum appears abnormally thin.  Muscle biopsy shows evidence of denervation atrophy.

Genetics

Homozygous or compound heterozygous mutations in the TBCE gene (1q42.3) can cause this disorder.  

Biallelic mutations in the same gene also cause Kenny-Caffey syndrome type 1 (244460) and a hypoparathyroidism dysmorphism syndrome (241410).

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No treatment has been reported.

References
Article Title: 

TBCE Mutations Cause Early-Onset Progressive Encephalopathy with Distal Spinal Muscular Atrophy

Sferra A, Baillat G, Rizza T, Barresi S, Flex E, Tasca G, D'Amico A, Bellacchio E, Ciolfi A, Caputo V, Cecchetti S, Torella A, Zanni G, Diodato D, Piermarini E, Niceta M, Coppola A, Tedeschi E, Martinelli D, Dionisi-Vici C, Nigro V, Dallapiccola B, Compagnucci C, Tartaglia M, Haase G, Bertini E. TBCE Mutations Cause Early-Onset Progressive Encephalopathy with Distal Spinal Muscular Atrophy. Am J Hum Genet. 2016 Oct 6;99(4):974-983.

PubMed ID: 
27666369

Biallelic Mutations in TBCD, Encoding the Tubulin Folding Cofactor D, Perturb Microtubule Dynamics and Cause Early-Onset Encephalopathy

Flex E, Niceta M, Cecchetti S, Thiffault I, Au MG, Capuano A, Piermarini E, Ivanova AA, Francis JW, Chillemi G, Chandramouli B, Carpentieri G, Haaxma CA, Ciolfi A, Pizzi S, Douglas GV, Levine K, Sferra A, Dentici ML, Pfundt RR, Le Pichon JB, Farrow E, Baas F, Piemonte F, Dallapiccola B, Graham JM Jr, Saunders CJ, Bertini E, Kahn RA, Koolen DA, Tartaglia M. Biallelic Mutations in TBCD, Encoding the Tubulin Folding Cofactor D, Perturb Microtubule Dynamics and Cause Early-Onset Encephalopathy. Am J Hum Genet. 2016 Oct 6;99(4):962-973.

PubMed ID: 
27666370

Neurodegeneration with Ataxia, Dystonia, and Gaze Palsy, Childhood-Onset

Clinical Characteristics
Ocular Features: 

Vertical gaze palsy has its onset between 7 and 15 years of age.   Nystagmus and oculomotor apraxia are often present.

Systemic Features: 

Onset of unsteadiness, gait ataxia, and cognitive decline are evident in the first or second decades of life.  Dysdiadokinesis, dysarthria, dysmetria, dystonia, athetotic movements, signs of Parkinsonism with tremor may also be present.  Some patients have a mild hearing loss.  Tissue from muscle biopsies are normal.  Brain imaging reveals cerebellar atrophy in some families and iron deposition in the basal ganglia in others.

Many patients are wheelchair-bound eventually.

Genetics

Homozygous mutations in the SQSTM1 gene (5q35.3) are responsible for this condition. 

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No treatment has been reported but physical therapy, speech therapy, and special education may be of benefit.

References
Article Title: 

Absence of the Autophagy Adaptor SQSTM1/p62 Causes Childhood-Onset Neurodegeneration with Ataxia, Dystonia, and Gaze Palsy

Haack TB, Ignatius E, Calvo-Garrido J, Iuso A, Isohanni P, Maffezzini C, Lonnqvist T, Suomalainen A, Gorza M, Kremer LS, Graf E, Hartig M, Berutti R, Paucar M, Svenningsson P, Stranneheim H, Brandberg G, Wedell A, Kurian MA, Hayflick SA, Venco P, Tiranti V, Strom TM, Dichgans M, Horvath R, Holinski-Feder E, Freyer C, Meitinger T, Prokisch H, Senderek J, Wredenberg A, Carroll CJ, Klopstock T. Absence of the Autophagy Adaptor SQSTM1/p62 Causes Childhood-Onset Neurodegeneration with Ataxia, Dystonia, and Gaze Palsy. Am J Hum Genet. 2016 Sep 1;99(3):735-43.

PubMed ID: 
27545679

Cerebellar Atrophy, Visual Impairment, and Psychomotor Retardation

Clinical Characteristics
Ocular Features: 

Patients usually have deep-set eyes.  Cortical visual impairment has been described in one patient but optic atrophy has been seen in another.  The VEP and ERG are described as 'abnormal'.  Strabismus, hyperopia, and myopia are sometimes seen.

Systemic Features: 

Progressive microcephaly is often noted.  Truncal hypotonia and scoliosis may be present while muscle tone is increased in the extremities in the presence of diminished deep tendon reflexes in other patients.  Dystonic posturing occurs in some families.  Gingival hyperplasia is a common feature and retrognathia is often present.

Brain imaging reveals progressive cerebellar atrophy and a foreshortened corpus callosum in all families.  Various degrees of cerebral atrophy have been identified while intellectual disability may be marked.  Speech delay is common.

Genetics

This is an autosomal recessive condition associated with homozygous mutations in the EMC1 gene (1p36.13).

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No treatnent has been reported.

References
Article Title: 

Monoallelic and Biallelic Variants in EMC1 Identified in Individuals with Global Developmental Delay, Hypotonia, Scoliosis, and Cerebellar Atrophy

Harel T, Yesil G, Bayram Y, Coban-Akdemir Z, Charng WL, Karaca E, Al Asmari A, Eldomery MK, Hunter JV, Jhangiani SN, Rosenfeld JA, Pehlivan D, El-Hattab AW, Saleh MA, LeDuc CA, Muzny D, Boerwinkle E; Baylor-Hopkins Center for Mendelian Genomics, Gibbs RA, Chung WK, Yang Y, Belmont JW, Lupski JR. Monoallelic and Biallelic Variants in EMC1 Identified in Individuals with Global Developmental Delay, Hypotonia, Scoliosis, and Cerebellar Atrophy. Am J Hum Genet. 2016 Mar 3;98(3):562-70.

PubMed ID: 
26942288

Mitochondrial Short-Chain Enoyl-CoA Hydratase 1 Deficiency

Clinical Characteristics
Ocular Features: 

The ocular phenotype has not been thoroughly studied.  Nystagmus has been reported in several infants.

Systemic Features: 

Evidence of severe psychomotor retardation is evident at birth or shortly thereafter.  Neonatal hypotonia with a poor suck reflex and episodic apnea is evident.  Spasticity may become evident later.  Brain imaging shows T-weighted hyperintensity areas in the basal ganglia resembling Leigh syndrome lesions.  The corpus callosum appears thin.  Serum and CSF lactate is elevated and decreased activity of the pyruvate dehydrogenase complex is present.

Infants do not achieve normal developmental milestones such as speech or sitting unsupported and several have died early in childhood from cardiorespiratory failure, possibly related to a combined mitochondrial respiratory chain dysfunction.

Genetics

The transmission pattern in several families is consistent with autosomal recessive inheritance.  Compound heterozygous mutations have been found in the ECHS1 gene (10q26.3).

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No treatment has been reported.

References
Article Title: 

Adrenoleukodystrophy, X-Linked

Clinical Characteristics
Ocular Features: 

Virtually all patients have visual symptoms.  Loss of acuity, hemianopia, visual agnosia, optic atrophy, and strabismus are the most common features.   Neuropathy may cause a decrease in corneal sensation.  Gaze abnormalities due to ocular apraxia are sometimes seen.  Ocular symptoms often occur after the systemic abnormalities are noted.  However, there is considerable heterogeneity in age of onset and progression of symptoms.

Histopathology of ocular structures reveals characteristic inclusions in retinal neurons, optic nerve macrophages, and the loss of ganglion cells with thinning of the nerve fiber layer of the retina. 

Systemic Features: 

This is a peroxisomal disorder of very-long-chain fatty acid (VLCF) metabolism that leads to progressive neurological and adrenal dysfunction from accumulation of VLCFAs in the nervous system, adrenal glands, and testes.  The age of onset and clinical course are highly variable and there may be several forms.  The childhood form begins between the ages of 4 and 8 years but in other patients with the adult form, symptoms may not appear until the third decade of life.  A viral illness may precipitate the onset.   Symptoms of both central and peripheral neurologic disease are often present with cognitive problems, ataxia, spasticity, aphasia, and loss of fine motor control.  Hearing loss is seen in some patients.  Younger patients tend to have more behavioral problems while older individuals may develop dementia.

Adrenal insufficiency leads to skin hyperpigmentation, weakness, loss of muscle mass and eventually coma.  Impotence in males is common. 

Genetics

This is an X-linked disorder secondary to mutations in the ABCD1 gene (Xp28).  The result is a deficiency in the cellular transporter known as adrenoleukodystrophy protein that is active in perioxosomes.

Although this X-linked disorder is primarily manifest in males, between 20 and 50% of female carriers have at least some symptoms, usually with a later onset than seen in males.

There are also rare cases with an apparent autosomal recessive pattern of inheritance (NALD) (202370) having an earlier onset and more aggressive course. 

Pedigree: 
X-linked recessive, carrier mother
X-linked recessive, father affected
Treatment
Treatment Options: 

Treatment of adrenal insufficiency is important and can be lifesaving.  Low vision aids, physical therapy and special education may be helpful.  Some young patients with early disease have benefitted from bone marrow transplantation.  "Lorenzo's Oil" (a mixture of oleic acid and erucic acid) has been reported to reduce or delay symptoms in some boys.

Recent reports suggest new treatment modalities may hold promise.  Infusion of autologous CD34+ cells transduced with the Lentin-D lentiviral vector reduced major symptoms in 15 of 17 boys within 29 months after treatment.  Likewise, intrathecal baclofen treatment in two boys with rapidly advancing cerebral manifestations provided symptomatic and palliative improvement.

 

References
Article Title: 

Hematopoietic Stem-Cell Gene Therapy for Cerebral Adrenoleukodystrophy

Eichler F, Duncan C, Musolino PL, Orchard PJ, De Oliveira S, Thrasher AJ, Armant M, Dansereau C, Lund TC, Miller WP, Raymond GV, Sankar R, Shah AJ, Sevin C, Gaspar HB, Gissen P, Amartino H, Bratkovic D, Smith NJC, Paker AM, Shamir E, O'Meara T, Davidson D, Aubourg P, Williams DA. Hematopoietic Stem-Cell Gene Therapy for Cerebral Adrenoleukodystrophy. N Engl J Med. 2017 Oct 4. doi: 10.1056/NEJMoa1700554. [Epub ahead of print].

PubMed ID: 
28976817

X-linked adrenoleukodystrophy

Moser HW, Mahmood A, Raymond GV. X-linked adrenoleukodystrophy. Nat Clin Pract Neurol. 2007 Mar;3(3):140-51. Review.

PubMed ID: 
17342190

Sandhoff Disease

Clinical Characteristics
Ocular Features: 

Retinal ganglion cells are rendered dysfunctional from the toxic accumulation of intra-lysosomal GM2 ganglioside molecules causing early visual symptoms.  These cells in high density around the fovea centralis create a grayish-white appearance.  Since ganglion cells are absent in the foveolar region, this area retains the normal reddish appearance, producing the cherry-red spot.  Axonal decay and loss of the ganglion cells leads to optic atrophy and blindness. 

Systemic Features: 

Sandhoff disease may be clinically indistinguishable from Tay-Sachs disease even though the same enzyme is defective (albeit in separate subunits A and B that together comprise the functional enzymes).  The presence of hepatosplenomegaly in Sandoff disease may be distinguishing. The infantile form of this lysosomal storage disease seems to be the most severe.  Infants appear to be normal until about 3-6 months of age when neurological development slows and muscles become weak.  Seizures, loss of interest, and progressive paralysis begin after this together with loss of vision and hearing.  An exaggerated startle response is considered an early and helpful sign in the diagnosis.  Among infants with early onset disease, death usually occurs by 3 or 4 years of age.   

Ataxia with spinocerebellar degeneration, motor neuron disease, dementia, and progressive dystonia are more common in individuals with later onset of neurodegeneration.  The juvenile and adult-onset forms of the disease also progress more slowly.  

Genetics

Sandhoff disease results from mutations in the beta subunit of the hexosaminidase A and B enzymes.  It is an autosomal recessive disorder caused by mutations in HEXB (5q13). 

Tay-Sachs disease (272800) can be clinically indistinguishable from Sandoff disease and they are allelic disorders.  However, the mutation in Tay-Sachs (272800) is in HEXA resulting in dysfunction of the alpha subunit of hexosaminidase A enzyme. 

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No specific treatment is available beyond general support with proper nutrition and maintainence of airways.  Anticonvulsants may be helpful in some stages.  Gene therapy in fibroblast cultures has achieved some restoration of  hexosaminidase A activity in Tay-Sachs disease and may have potential in Sandhoff disease as well. 

References
Article Title: 

Neuronal Ceroid Lipofuscinoses

Clinical Characteristics
Ocular Features: 

At least 13 genotypically distinct forms of neuronal ceroid lipofuscinosis have been described.  The ocular features are highly similar in all forms with blindness the end result in all types (although not all cases with an adult onset suffer vision loss).  The onset of visual signs and symptoms is highly variable.  Optic atrophy is the most common finding which may occur as early as two years of age in the infantile form.  Night blindness is a symptom in those with a later onset but panretinal degeneration with unrecordable ERGs eventually occurs.  Pigmentary changes throughout the retina are often seen and sometimes occur in a bull’s-eye pattern.  Retinal blood vessels may be attenuated and lens opacities of various types are common. 

Systemic Features: 

The neuronal ceroid lipofuscinosis are a group of inherited neurodegenerative lysosomal-storage disorders characterized by the intracellular accumulation of autofluorescent lipopigment causing damage predominantly in the central nervous system.  The result is a progressive encephalopathy with cognitive and motor decline, eventual blindness, and seizures with early death.  While early descriptions distinguished several types based primarily on age of onset, genotyping has now identified responsible mutations in at least 10 genes and time of onset is no longer considered a reliable indicator of the NCL type. 

Genetics

The NCLs are usually inherited in autosomal recessive patterns with the exception of some adult onset cases in which an autosomal dominant pattern is sometimes seen.

The various forms of NCL are often divided according to ages of onset but overlap is common.  Thus the congenital form (CLN10; 610127), caused by a mutation in the CTSD gene at 11p15.5, can have an onset of symptoms at or around birth but also is responsible for an adult form (Vida infra).  The CLN1 infantile form (256730), caused by a mutation in the PPT1 gene at 1p32, has an onset between 6 and 24 months  There are several mutations causing late infantile disease (CLN2, 204500) involving the TPP1 gene (11p15.5) leading to symptoms between 2-4 years, the CLN5 gene (256731) at 13q21.1-q32 with onset between 4 and 7 years, the CLN6 gene (601780) at 15q21-q23 showing symptoms between 18 months and 8 years, and the CLN8 gene (610003) at 8p23 with symptoms beginning between 3 and 7 years.  Another early juvenile form (CLN7; 610951) is caused by mutations in MFSD8 (4q228.1-q28.2).

A juvenile form (sometimes called Batten disease or Spielmeyer-Vogt with onset between 4 and 10 years results from mutations in CLN3 (204200) as well as in TPP1, PPT1, and CLN9 (609055).  An adult form known as ANCL or Kuf’s disease results from mutations in CTSD, PPT, CLN3, CLN5, and CLN4 (204300) and has its onset generally between the ages of 15 and 50 years. 

Homozygous mutations in the ATP13A2 gene (1p36.13), known to cause Kufor-Rakeb type parkinsonism (606693), have also been found in NCL.

Pedigree: 
Autosomal dominant
Autosomal recessive
Treatment
Treatment Options: 

Treatment is primarily symptomatic for sleep disorders, seizures, psychoses, malnutrition, dystonia and spasticity.  However, there is recent progress in the application of enzyme-replacement therapies in the soluble lysosomal forms of CNL.  Gene therapies and the use of stem cells also hold promise. 

References
Article Title: 

Tay-Sachs Disease

Clinical Characteristics
Ocular Features: 

Retinal ganglion cells become dysfunctional as a result of the toxic accumulation of intra-lysosomal GM2 ganglioside molecules causing early visual symptoms.  These cells in high density around the fovea centralis create a grayish-white appearance.  Since ganglion cells are absent in the foveolar region, this area retains the normal reddish appearance, producing the cherry-red spot.  Axonal decay and loss of the ganglion cells leads to optic atrophy and blindness.

Systemic Features: 

Sandoff disease may be clinically indistinguishable from Tay-Sachs disease even though the same enzyme is defective (albeit in separate subunits A and B that together comprise the functional hexosaminidase enzyme).   The infantile form of this lysosomal storage disease is the most common.  Infants appear to be normal until about 3-6 months of age when neurological development slows and muscles become weak.  Seizures, loss of interest, and progressive paralysis begin after this together with loss of vision and hearing.  The facies are coarse and the tongue is enlarged.  An exaggerated startle response is considered an early and helpful sign in the diagnosis.  Hepatosplenomegaly is usually not present.  Among infants with early onset disease, death usually occurs by 3 or 4 years of age.     

Ataxia with spinocerebellar degeneration, motor neuron disease, and progressive dystonia are more common in individuals with later onset of neurodegeneration.  The juvenile and adult-onset forms of the disease also progress more slowly.

Genetics

Tay-Sachs disease is an autosomal recessive disorder caused by mutations in the hexosaminidase A gene, HEXA, (15q23-q24).  The altered enzyme is unable to break down GM2 ganglioside which accumulates in lysosomes and leads to neuronal death.

A related form, clinically and biochemically similar to Tay-Sachs disease , is GM2-gangliosidosis (272750) but it is caused by mutations in GM2A (5q31.3-q33.1) with normal hexosaminidase A and B.  Sandhoff disease (268800) is clinically indistinguishable but caused by mutations in the beta subunit of hexosaminidase (HEXB) A and B at 5q13. 

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

Treatment is largely supportive.  Anticonvulsant pharmaceuticals may help in the control of seizures but require frequent modifications as the neuronal degeneration progresses.  Airways and nutrition maintainence are important.

Application of gene therapy to cell cultures have shown promise in restoring enzyme function and may someday lead to human treatment. 

    

References
Article Title: 

Tay-Sachs disease

Fernandes Filho JA, Shapiro BE. Tay-Sachs disease. Arch Neurol. 2004 Sep;61(9):1466-8. Review.

PubMed ID: 
15364698

Niemann-Pick Disease, Types C1 (D)

Clinical Characteristics
Ocular Features: 

The predominant ocular sign in types C1 is difficulty in upgaze described as a supranuclear palsy.  Abnormal saccadic movements have been reported as well.  Retinal signs such as a cherry red spot are not common.

Systemic Features: 

Hepatosplenomegaly and cognitive decline are similar in nature to those found in Niemann-Pick disease types A and B.  Types C1 and C2 are clinically similar but discussed separately as they are caused by mutations in separate genes.  Type D is caused by the same mutation causing C1.  Onset of disease manifested by ataxia, seizures and spasticity is usually between 2 and 4 years.  Dystonia, intention tremor, dysarthria, and hepatosplenomegaly are other features but visceral involvement may be absent.  Ascites and jaundice are sometimes present.  Dementia and extrapyramidal signs are often seen later.  However, there is considerable variation in onset and progression of disease but the symptoms are generally milder than that in types A and B.

Genetics

Type C1 (and D) are caused by mutations in the NPC1 gene (18q11-q12), and type C2 (607625) by mutations in the NPC2 gene (14q24.3).  Mutations in C1 are far more common (95%) than C2 mutations.  The gene mutations reduce the efficiency of sphingosine efflux from lysosomes and late endosomes as a result of a defect in esterification of cholesterol.

Types A (257200) and B (607616) Niemann-Pick disease generally cause more severe clinical signs and are the result of a sphingomyelinase deficiency.  All types of Niemann-Pick disease follow autosomal recessive patterns of inheritance.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

It has recently been reported that intrathecal 2-hydroxypropyl-beta-cyclodextrin slows progression of clinical symptoms and prolonged lifespan.

References
Article Title: 

Intrathecal 2-hydroxypropyl-β-cyclodextrin decreases neurological disease progression in Niemann-Pick disease, type C1: a non-randomised, open-label, phase 1-2 trial

Ory DS, Ottinger EA, Farhat NY, King KA, Jiang X, Weissfeld L, Berry-Kravis E, Davidson CD, Bianconi S, Keener LA, Rao R, Soldatos A, Sidhu R, Walters KA, Xu X, Thurm A, Solomon B, Pavan WJ, Machielse BN, Kao M, Silber SA, McKew JC, Brewer CC, Vite CH, Walkley SU, Austin CP, Porter FD. Intrathecal 2-hydroxypropyl-v-cyclodextrin decreases neurological disease progression in Niemann-Pick disease, type C1: a non-randomised, open-label, phase 1-2 trial. Lancet. 2017 Aug 10. pii: S0140-6736(17)31465-4. doi: 10.1016/S0140-6736(17)31465-4. [Epub ahead of print].

PubMed ID: 
28803710

Niemann-Pick disease type C

Vanier MT, Millat G. Niemann-Pick disease type C. Clin Genet. 2003 Oct;64(4):269-81. Review.

PubMed ID: 
12974729

Niemann-Pick Disease, Types A and B

Clinical Characteristics
Ocular Features: 

Affected infants usually develop prominent cherry red spots during the first 12 months of life and the entire retina has an ‘opaque’ appearance.  Intracellular lipid accumulation has been seen in retinal neurons, amacrine cells, retinal pigment epithelial cells, and receptors.  The cornea has stromal haziness.  The lens has a brownish coloration on the anterior surface with white spots on the posterior capsule.  Lens opacification seems to progress.

Vision in the first year of life is likely normal as infants have normal fixation, pupillary reactions, and following movements with no nystagmus.  However, by about 2 years of age visual responsiveness may be lost.

Systemic Features: 

Both the age of onset of neurological symptoms and the rate of progression are highly variable. Type A, known as the infantile form, is the more severe disease with onset by 6 months of age with rapid progression and few patients survive beyond three years of age.  Neonates seem to develop normally for the first 6 months but then become irritable, fail to thrive and feed poorly.  Hepatosplenomegaly is usually the first physical sign.  Hypotonia and pulmonary infections are common.  These patients never achieve normal developmental milestones such as sitting, walking or crawling and the neurodegeneration is relentless from this point with the median age at death 21 months, usually from respiratory disease.

The less severe form of Niemann-Pick disease, type B, has a later onset and slower course.  Such patients have widespread visceral disease affecting liver, spleen and lungs with hyperlipidemia but few neurologic symptoms and often survive into adulthood.  Mutations in the same gene are involved, however.  

Other rare cases have intermediate disease and some have proposed these be classified as types E and F but the phenotypes have not been well characterized.  The benefits of such a classification system are questionable as all result from mutations in the same gene simply illustrating the range in the clinical spectrum.

Sphingomyelin and other lipids accumulate in cells of various types including neurons and reticuloendothelial cells accounting for the hepatosplenomegaly and neurodegeneration.  Sphingomyelinase deficiency can be demonstrated in leukocytes and cultured fibroblasts.

Genetics

This is an autosomal recessive neurodegenerative disorder resulting from homozygous mutations in SMPD1 (11p15.4-p15.1) encoding sphingomyelin phosphodiesterase-1.  This recessive gene has an unusual biology.  Only the maternally inherited allele is active in the homozygous condition.  Such parent-specific gene activation is called gene imprinting.

Types A and B are allelic disorders.  

Niemann-Pick diseases designated types C1 and D (257220) are caused by mutations in the NPC1 gene (18q11-q12) and type C2 (607625)  from mutations in the NPC2 gene (14q24.3).

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

Enzyme replacement therapy trials are underway.  Amniotic membrane, bone marrow, and stem cell transplantation have been tried with some improvement in visceral disease but the results are mixed and await further studies.

References
Article Title: 

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