CASE PRESENTATION

Maternal Uniparental Isodisomy Causing Autosomal RecessiveGM1 Gangliosidosis: A Clinical Report

Jessica E. King & Amy Dexter & Inder Gadi & Val Zvereff &Meaghan Martin & Miriam Bloom & Adeline Vanderver &

Amy Pizzino & Johanna L. Schmidt

Received: 13 October 2013 /Accepted: 25 March 2014# National Society of Genetic Counselors, Inc. 2014

Abstract Uniparental disomy is a genetic cause of diseasethat may result in the inheritance of an autosomal recessivecondition. A child with developmental delay and hypotoniawas seen and found to have severely abnormal myelination.Lysosomal enzyme testing identified an isolated deficiency ofbeta-galactosidase. Subsequently, homozygous missense mu-tations in the galactosidase, beta 1 (GLB1) gene on chromo-some 3 were found. Parental testing confirmed inheritance oftwo copies of the same mutated maternal GLB1 gene, and nopaternal copy. SNP analysis was also done to confirm pater-nity. The patient was ultimately diagnosed with autosomalrecessive GM1 gangliosidosis caused by maternal uniparentalisodisomy. We provide a review of this patient and others inwhich uniparental disomy (UPD) of a non-imprinted chromo-some unexpectedly caused an autosomal recessive condition.This is the first case of GM1 gangliosidosis reported in theliterature to have been caused by UPD. It is important forgenetic counselors and other health care providers to be awareof the possibility of autosomal recessive disease caused byUPD. UPD as a cause of autosomal recessive disease drasti-cally changes the recurrence risk for families, and discussionssurrounding UPD can be complex. Working with families tounderstand UPD when it occurs requires a secure and trustingcounselor-family relationship.

Keywords Autosomal recessive . Uniparental disomy .

Isodisomy . GM1 gangliosidosis .GLB1

Introduction

Cases of uniparental disomy (UPD) have been reportedthroughout the literature, both in the context of heterodisomy(i.e. when two inherited homologous chromosomes comefrom one parent but are not identical) and in the context ofisodisomy (i.e. when two inherited homologous chromosomescome from one parent and are identical) (Engel 1995; Engel2005; Stratchan and Read 2001). Most often the UPD inher-itance pattern in human disease occurs in association withdefects in imprinting, such as with Angelman syndrome orPrader Willi syndrome (Nussbaum et al. 2007). In these cases,UPD leads to problems with gene expression from the appro-priate parent of origin. Chromosomes with known imprintedgenes, in which both a maternal and a paternal copy is neces-sary for proper gene expression, include chromosomes 6, 7,11, 14, 15, and 20.

UPD can be implicated in other human disease on non-imprinted genes as well, in particular in cases of uniparentalisodisomy when the parent of origin is a carrier of an autoso-mal recessive mutation and a child inherits two identical,mutated copies from one parent (isodisomy). We report abouta patient in which this occurred in a patient with gangliosidemonosialotetrahexosyl (GM1) gangliosidosis resulting frommaternal isodisomy of chromosome 3, as well as provide areview of other disorders in which this mechanism of inheri-tance has been implicated.

Materials and Methods

The reported patient was enrolled in an IRB approvedbiorepository for patients with leukodystrophies andleukoencephalopathies. Records were reviewed and are pre-sented below. All interventions in this patient were part of

J. E. King :M. Bloom :A. Vanderver (*) :A. Pizzino :J. L. SchmidtDepartment of Neurology, Children’s National Medical Center, 111Michigan Ave. NW, Washington, DC 20010, USAe-mail: avanderv@childrensnational.org

A. Dexter : I. Gadi :V. Zvereff :M. MartinLaboratory Corporation of America, Research Triangle Park, NC,USA

J Genet CounselDOI 10.1007/s10897-014-9720-9

standard clinical care and standard clinical laboratoryprocedures.

Cases of unipaternal disomy were identified in the literatureby searching PubMed with the key words “uniparental +disomy,” “uniparental + isodisomy,” “maternal + disomy,”“maternal + isodisomy,” “paternal + disomy,” and “paternal +isodisomy.” Manuscripts were reviewed for cases in whichautosomal recessive heritable disorders were caused byunipaternal isodisomy.

Results

Case Report The patient was a 1 ½-year-old female born tonon-consanguineous parents. Family history was unremark-able. She was born at 38 weeks with a normal vaginaldelivery.

She was first seen in the context of developmental and grossmotor delay because she was not yet able to sit independentlyat the age of 6 months and there were concerns of hypotoniafrom her pediatrician. At this age, she was unable to transferobjects from one hand to another and was reluctant to bearweight on her legs when held up. She was able to sit, but withmaximal support, was reaching and grabbing objects, able tolift her head and neck up, but not her chest. The patient wasalso able to bring her hands together and used both of herhands evenly, with a tendency to roll more to the right than tothe left. The parents reported an exaggerated startle response.

A brain MRI at 7 months revealed severely abnormalmyelination in the child. There was markedly delayedmyelination, with a myelination pattern equivalent to a normalnewborn. There was also concern for an early cherry red spoton neuro-ophthalmologic evaluation. Lysosomal enzyme test-ing identified an isolated deficiency of beta-galactosidase,supportive of a diagnosis of infantile GM1 gangliosidosis(Type I).

Subsequent genetic testing identified apparently homozy-gous missense mutations (c.1038G > C, p.Lys346Asn) in thegalactosidase, beta 1 (GLB1) gene on chromosome 3,

confirming this diagnosis. Parental enzyme testing was com-pleted and the mother was found have decreased beta-galactosidase enzyme in the carrier range, while the fatherhad normal beta-galactosidase enzyme levels.

Considering the homozygous mutation in the context ofnormal paternal beta-galactosidase enzyme, the possibility ofmaternal UPD was considered. Although it was considered,the possibility of non-paternity had not seemed to be a likelysituation for this family. Molecular analysis was performed ata standard clinical laboratory using polymorphic DNAmarkers for chromosome 3, which subsequently confirmedthe inheritance of two identical maternal copies of chromo-some 3 in the patient (Fig. 1). Non-paternity was excluded bycomparing DNA alleles from chromosome pairs other thanchromosome 3. The patient was found to have biparentalinheritance for other chromosome homologues according tostandard clinical diagnostic approaches.

Review of the Literature The literature was reviewed to deter-mine the number of cases reported of uniparental disomycausing an autosomal recessive disorder. There are at least45 cases reported in the literature and they are reviewed inTable 1. This table summarizes information about the affectedchromosome, the gene, if this was maternal or paternal UPD,and the resulting disease. The corresponding genes involvedin these diseases are depicted in Table 2. All diseases includedin this table are due to autosomal inheritance and are not to animprinting mechanism.

Discussion

This patient was found to have maternal uniparentalisodisomy after having been found to have apparently homo-zygous mutations in the galactosidase, beta 1 (GLB1) genecausing GM1 gangliosidosis. Results of the child’s moleculartesting and the parental enzyme were presented to the familysimultaneously, and the possibility of maternal UPD wasdiscussed at that time. Confirmatory UPD testing results wereprovided when they became available. Extensive discussions

Fig. 1 Demonstration ofunipaternal isodisomy.Microsatellite analysis of theproband and parental DNA atD3S1766 and D3S3045 showsthat the child inherited only onematernal allele and the paternalalleles were excluded

King et al.

Table 1 Cases of uniparental disomy causing an autosomal recessive disorder

Reference Chromosome Gene Maternal/Paternal

Disease caused

Nimmo et al. 2010 Chromosome 1 GNPAT Paternal Rhizomelic chronodrodysplasia punctata type 2

Schejbel et al. 2011 Chromosome 1 CFH Paternal Complement factor H deficiency andendocapillary glomerulonephritis

Turner et al. 2007 Chromosome 1 PEX Maternal Zellweger syndrome

Benko et al. 2008 Chromosome 1 MPZ GBA Paternal Charcot-Marie-Tooth and Gaucher disease type 3

Riveiro Alvarez et al. 2007 Chromosome 1 ABCA4 Paternal Stargardt disease

Roberts et al. 2012 Chromosome 1 CD45 Maternal CD45-deficient severe combined immunodeficiency

Castori et al. 2008 Chromosome 1 LAMB3 Maternal Herlitz junctional epidermolysis bullosa

Fassihi et al. 2005 Chromosome 1 LAMB3 Paternal Herlitz junctional epidermolysis bullosa

Dufourcq Lagelouseet al. 1999

Chromosome 1 LYST Maternal Chediak-Higashi syndrome

Gelb et al. 1998 Chromosome 1 CTSK Paternal Pycnodysostosis

Miura et al. 2000 Chromosome 1 TRKA Paternal Congenital insensitivity to pain with anhidrosis

Rivolta et al. 2002 Chromosome 1 USH2A Paternal Retinitis pigmentosa

Thompson et al. 2002 Chromosome 1Chromosome 2

RPE65 MERTK Paternal Reintal dystrophy

Giovannoni et al. 2012 Chromosome 2 ABCB11 Paternal Bile salt export pump deficiency

Lopez Garrido et al. 2009 Chromosome 2 CYP1B1 Paternal Primary congenital glaucoma

Castiglia et al. 2009 Chromosome 2 ABCA12 Paternal Harlequin ichthyosis

Baskin et al. 2010 Chromosome 2 HADHA Paternal Long chain 3-hydroxyacyl-CoAdehydrogenase (LCHAD) deficiency

Haudry et al. 2012 Chromosome 2 DGUOK Maternal Hepatocerebral mitochondrial DNA depletion syndrome

Bakker et al. 2001 Chromosome 2 TPO Maternal Congenital hypothyroidism

Hamvas et al. 2009 Chromosome 2Chromosome 16

SFTPB ABCA3 Maternal Paternal Inherited surfactant deficiency

Douglas et al. 2011 Chromosome 2Chromosome 22

DGUOK TYMP Paternal Maternal Autosomal recessive mitochondrial DNAdepletion syndrome

Matejas et al. 2011 Chromosome 3 LAMB2 Paternal Pierson syndrome

Fassihi et al. 2006 Chromosome 3 COL7A1 Maternal Recessive dystrophic epidermolysis bullosa

Ding et al. 2012 Chromosome 4 FGB Maternal Hypodysfibrinogenaemia

Aminoff et al. 2012 Chromosome 4 MTTP Maternal Abetalipoproteinemia

Cottrell et al. 2012 Chromosome 4 SGCB Maternal Limb-girdle muscular dystrophy 2E

Brzustowicz et al. 1994 Chromosome 5 Specific geneunknown

Paternal Spinal muscular atrophy

Gumus et al. 2010 Chromosome 6 MOCS1 Maternal Molybdenum cofactor (MoCo) deficiency

Sasaki et al. 2011 Chromosome 6 CUL7 Maternal 3 M syndrome

Abramowicz et al. 1994 Chromosome 6 MUT Paternal Methylmalonic acidemia and agenesis of pancreaticbeta cells causing diabetes millitus

Spence et al. 1988 Chromosome 7 CFTR Maternal Cystic fibrosis

Le Caignec et al. 2007 Chromosome 7 CFTR Paternal Cystic fibrosis

Benlian et al. 1996 Chromosome 8 LPL Paternal Familial chylomicronemia

Sulisalo et al. 1997 Chromosome 9 CHH Maternal Cartilage-hair hypoplasia

Castanet et al. 2010 Chromosome 9 FOXE1 Maternal Syndromic congenital hypothyroidism

Boisseau et al. 2011 Chromosome 12 VWF Maternal Willebrand disease type 3

Anesi et al. 2011 Chromosome 13 SACS Paternal Autosomal recessive spastic ataxia ofcharlevoix-saguenay (ARSACS)

Ceballos Picot et al. 2011 Chromosome 16 APRT Maternal Adenine phosphoribosyltransferase deficiency

Catarzi et al. 2012 Chromosome 16 GALNS Maternal Morquio A syndrome

Lebre et al. 2009 Chromosome 17 CTNS Maternal Nephropathic cystinosis

Natsuga et al. 2010 Chromosome 17 ITGB4 Paternal Epidermolysis bullosa with pyloric atresia

Niida et al. 2012 Chromosome 22 ARSA Paternal Metachromatic leukodystrophy

Unipaternal Isodisomy in GM1 Gangliosidosis

with the family over several months helped to answer theirquestions and help themmake sense of these results, acknowl-edging expressed feelings of maternal guilt and implicationsfor future children and other family members. Although sur-prised and frustrated by this situation, the family demonstratedunderstanding of these results.

GM1 gangliosidosis occurs in 1 in 100,000 to 200,000newborns. The GLB1 gene provides instructions for makingthe enzyme beta-galactosidase, which is located in the lyso-somes to break down GM1 ganglioside. GM1 ganglioside isimportant for normal functioning of the neurons. A mutationin the GLB1 gene leads to a toxic accumulation of beta-galactosidase, especially in the brain, leading to progressivedamage of the neurons and other cells in which the substrateaccumulates. This leads to developmental regression and asthe disease progresses, individuals usually develophepatosplenomegaly, skeletal abnormalities, seizures, pro-found intellectual disability, and cherry-red spots due to retinalsubstrate accumulation. In some cases, affected individualshave distinct facial features, gingival hypertrophy, and/orcadiomyopathy. Signs and symptoms may differ dependingon age of onset (infantile (Type I), juvenile (Type II), or adult(Type III)).

Although, other cases of UPD of chromosome 3 have beenreported (see Table 1), this is the only patient described in theliterature with GM1 gangliosidosis as a result of UPD (Fassihiet al. 2006; Matejas et al. 2011). Uniparental disomy usuallyarises from an error in cell division during meiosis resulting inabnormal gametes. Gametes that are missing a copy of achromosome, from an error in meiosis II, will lead to aconception with a single copy of that chromosome, receivedfrom the one parent. Sometimes the single chromosome willduplicate (monosomy rescue mechanism) resulting inisodisomy. Monosomic rescue, however is not the only wayUPD can occur; a trisomic rescue can also occur, but thiswould lead to heterodisomy.

Through an extensive literature search, forty-four cases ofan autosomal recessive disorder due to uniparental disomywere found (see Table 1). In all cases, the disease was notcaused by an imprinting mechanism. Because the recurrencerisk changes so drastically when the genetic cause of autoso-mal recessive disease is due to UPD (from 25 % to nearlyzero), the identification of this cause is crucial to providingaccurate genetic counseling.

Study Limitations

This is a report on one person and as such, the individualconclusions drawn may not be generalizable to a broaderpopulation. Additionally, although an extensive literaturesearch was conducted, there may be additional reports in theliterature that did not emerge based on our specific querymethods. There may also be additional cases of autosomalrecessive disease due to UPD that were not reported in theliterature, and, thus, recessive disease due to UPD may bemore prevalent than what exists in the literature.

Practice Implications

Although it is rare, it is important for medical professionalsand genetic counselors to remember that uniparental disomy isa possible explanation for the inheritance of an autosomalrecessive condition in non-imprinted chromosomes. A geneticdiagnosis of UPD leading to an autosomal recessive diseasedrastically changes the recurrence risk, from 25 % to nearlyzero, and this is crucial information for genetic counseling.Especially in cases in which a biochemical study is sufficientfor diagnosis, it may be important to pursue a genetic diagno-sis as well, for this reason.

In addition, by being cognizant of the possibility of UPDcausing a recessive condition, the genetic counselor can avoidpotentially damaging discussions with the family surroundingissues of non-paternity, which may be the immediate assump-tion made in a case such as ours. Revealing non-paternity canbe devastating to the family, and can be detrimental to rela-tionships, so genetic counselors should be careful about if,when, and how to approach a family about this issue (Leiken1995; Lucassen and Parker 2001; Ross 1996) In our case,based on discussions with the family prior to and during thetesting process, non-paternity did not seem to be a likelyscenario. We provided extensive genetic counseling, includ-ing education about how autosomal recessive diseases usuallyoccur, and provided opportunities for the family to offer thepossibility of non-paternity. We did not directly inquire aboutnon-paternity.

The relationship fostered between the patient and the fam-ily with the genetic counselor is essential for effective casemanagement by the genetic counselor. Establishing a secureand trusting relationship with the family gives the genetic

Table 1 (continued)

Reference Chromosome Gene Maternal/Paternal

Disease caused

Huang et al. 2012 Chromosome 22 CYB5R3 Maternal Congenital methemoglobinemia

Quan et al. 1997 X Chromosome DMD Maternal Duchenne muscular dystrophy

King et al.

counselor the opportunity to understand the family’s dynamicand level of understanding of genetic testing and its potentialto reveal evidence of non-paternity, as well as allow for morehonest conversation about complex results such as UPD(Eriksson and Nilsson 2008). In this case, our team had spenttime to establish the relationship and understand the familydynamic, allowing us to avoid a potentially damaging discus-sion about non-paternity. The relationship between the geneticcounselor and the family in this case allowed for productiveconversations about these complex results, which ultimatelywas beneficial to the family.

If UPD is determined to be the cause of a recessive condi-tion, the parent of origin may experience feelings of guilt andresponsibility for their child’s condition, and this was true inour case. Upon learning these results, the mother made state-ments indicating that she felt at fault. This is seen extensivelywith X-linked conditions and parents who are carriers of anautosomal dominant mutation that is inherited by their child(Lehmann et al. 2011; Kay and Kingston 2002). A commonfeeling shared by these individuals is that they have “donesomething bad” or “hurt” their child, and these feelings canalso extend to the grandparents who had ultimately passed themutation down to one of the parents of the affected child(Lehmann et al. 2011). These feelings of guilt will also playan important role in their future reproductive decisions, asmany of these parents will assume the worst possible out-come, which should be discussed with a genetic counselor(Kay and Kingston 2002). Additionally, it is important to notethat feelings of blame may manifest from the non-carrierparent (James et al. 2006), although this was not evident tous in our discussions with this family.

It is the role of the genetic counselor to discuss thesefeelings of guilt with the families, and help modify thesebeliefs and provide genetics education to alleviate these feel-ings of guilt. It has been found that statements about themhaving no control over the situation are usually not effective(e.g. “it was a chance event”) (Kessler et al. 1984). Certaintactics can then be used to relieve guilt, such as use ofauthority, normalization, reframing, and limiting liability(Kessler et al. 1984).

Table 2 Gene legend

Geneabbreviation

Gene name

GNPAT Glyceronephosphate O-acyltransferase

CFH Complement factor H

PEX Peroxisomal biogenesis factor

MPZ GBA Myelin proterin zero glucosidase, beta, acid

GNPAT Glyceronephosphate O-acyltransferase

ABCA4 ATP-binding cassette, sub-family A (ABC1), member 4

CD45 Also called PTPRC—protein tyrosine phosphatase,receptor type, C

LAMB3 Laminin, beta 3

LAMB3 laminin, beta 3

LYST Lysosomal trafficking regulator

CTSK Cathepsin K

TRKA Also called NTRK1—neurotrophic tyrosine kinase,receptor, type 1

USH2A Usher syndrome 2A (autosomal recessive, mild)

RPE65 Retinal pigment epithelium-specific protein 65 kDa

MERTK C-mer proto-oncogene tyrosine kinase

ABCB11 ATP-binding cassette, sub-family B (MDR/TAP),member 11

CYP1B1 Cytochrome P450, family 1, subfamily B, polypeptide 1

ABCA12 ATP-binding cassette, sub-family A (ABC1), member 12

HADHA Hydroxyacyl-CoA dehydrogenase/3-ketoacyl-CoAthiolase/enoyl-CoA hydratase (trifunctional protein),alpha subunit

DGUOK Deoxyguanosine kinase

TPO Thyroid peroxidase

SFTPB Surfactant protein B

ABCA3 ATP-binding cassette, sub-family A (ABC1), member 3

DGUOK Deoxyguanosine kinase

TYMP Thymidine phosphorylase

LAMB2 Laminin, beta 2 (laminin S)

COL7A1 Laminin, beta 2 (laminin S)

FGB fibrinogen beta chain

MTTP Fibrinogen beta chain

SGCB Sarcoglycan, beta (43 kDa dystrophin-associatedglycoprotein)

MOCS1 Molybdenum cofactor synthesis 1

MOCS2 Molybdenum cofactor synthesis 2

GEPH Gephyrin

CUL7 Cullin 7

MUT Methylmalonyl CoA mutase

CFTR Cystic fibrosis transmembrane conductance regulator(ATP-binding cassette sub-family C, member 7)

CFTR Cystic fibrosis transmembrane conductance regulator(ATP-binding cassette sub-family C, member 7)

LPL Lipoprotein lipase

CHH Cartilage hair hypoplasia

FOXE1 Forkhead box E1 (thyroid transcription factor 2)

VWF von Willebrand factor

SACS Spastic ataxia of Charlevoix-Saguenay (sacsin)

Table 2 (continued)

Geneabbreviation

Gene name

APRT Adenine phosphoribosyltransferase

GALNS Galactosamine (N-acetyl)-6-sulfate sulfatase

CTNS Cystinosin, lysosomal cystine transporter

ITGB4 Integrin, beta 4

ARSA Arylsulfatase A

CYB5R3 Cytochrome b5 reductase 3

DMD Dystrophin

Unipaternal Isodisomy in GM1 Gangliosidosis

These feelings are important to explore and a referral forfurther therapy should be considered in extreme cases. Due tothe complexity of uniparental disomy, patient understandingmay vary widely. It may be prudent to consider multiplesessions in order to ensure understanding as well as fosterthe counselor and patient relationship, as was done in thiscase.

Research Recommentations

More work needs to be done so that the occurrence rate ofUPD resulting in autosomal recessive disorders in the generalpopulation can be more precisely determined. This is impor-tant information to know and be able to provide to a familyduring a counseling session, particularly in determining theprobability of recurrence. The relevance of this knowledgewill increase as next generation sequencing approaches in-creasingly result in the identification of carrier states for raregenetic autosomal recessive disorders. The increasing use ofnext generation sequencing when trios are used may also aidin increasing the detection of UPD causing an autosomalrecessive disease.

Acknowledgments We acknowledge the family who provided clinicalinformation as part of the Myelin Disorders Bioregistry Project. We alsoacknowledge the support of the Delman fund in support of JK, and theDepartment of Neurology at Children’s National Medical Center.

Conflict of Interest Authors Jessica E. King, Amy Dexter, Inder Gadi,Val Zvereff, Meaghan Martin, Miriam Bloom, Adeline Vanderver, AmyPizzino, and Johanna L. Schmidt declare that they have no conflict ofinterest.

Informed Consent All procedures followed were in accordance withthe ethical standards of the responsible committee on human experimen-tation (institutional and national) and with the Helsinki Declaration of1975, as revised in 2000. Informed consent was obtained from all patientsbeing included in this study.

Human and Animal Rights No animal or human studies were carriedout by the authors for this article.

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