HMMAJ patients appear normal at birth. Most of them are soon presented to the pediatrician showing failure to thrive, developmental delays, and neurological symptoms [1] [2]. Symptom onset may, however, be delayed until adolescence [3]. The spectrum of neurological deficits described in HMMAJ patients is less broad than that reported for individuals suffering from other forms of homocystinuria with methylmalonic acidemia and is limited to lethargy, anomalies of muscle tone, respiratory distress and tachypnea, and seizures [1] [4] [3]. However, HMMAJ has been characterized as pathogenetically, biochemically and phenotypically similar to the cblF type [1] [3], so neurological symptoms ranging from cognitive impairment to movement disorders, apnea and decreased consciousness, and possibly psychiatric conditions and behavioral disorders may be expected in HMMAJ patients [4] [5]. Visual impairment due to retinal dystrophy may be detected in ophthalmological examinations [2]. Owing to extensive neurological disease, parents often describe feeding difficulties [1] [4].

With regard to extraneural manifestations, HMMAJ seems to be associated with an increased risk of cardiac malformations [4]. A single patient has been reported to have experienced a transient ischemic [3]. Beyond that, distinct cardiovascular complications have been observed in patients suffering from related disorders and may eventually occur in HMMAJ patients. Similarly, there are no case reports on renal involvement resulting in thrombotic microangiopathy and hemolytic uremic syndrome in HMMAJ patients even though kidney damage is a dreaded complication of related diseases [6]. Hyperpigmentation of the skin and hypopigmentation of the hair have been observed in two HMMAJ patients and it may be speculated that affected individuals could develop other dermatological symptoms [3] [7]. They are uncommon complications of cobalamin-related disorders such as homocystinuria with methylmalonic acidemia type cblC, but they are not unheard of.

It should be noted that there is only a handful of case reports on HMMAJ. Therefore, it is not possible to state whether there is a causal relationship between isolated clinical findings and ABCD4 mutations underlying HMMAJ [3].

• Poor Feeding

  The patient had feeding difficulties, poor growth, hypotonia, and developmental delay. [findzebra.com]

  Symptoms of a metabolic crisis include: poor feeding vomiting low muscle tone excessive sleepiness irritability rapid breathing muscle spasms If a metabolic crisis is not treated, seizures, stroke, coma, brain damage and sometimes death can occur. [newbornscreening.on.ca]

  The age of initial presentation of cblC ranges from (1) newborns who can be small for gestational age with unusually small head size; to (2) infants who can have poor feeding, failure to thrive, and neurologic/developmental abnormalities; to (3) toddlers [counsyl.com]

  […] difficulties Feeding problems Poor feeding [ more ] 0011968 Generalized hypotonia Decreased muscle tone Low muscle tone [ more ] 0001290 Growth delay Delayed growth Growth deficiency Growth failure Growth retardation Poor growth Retarded growth [ more [rarediseases.info.nih.gov]

  After birth, infants with this disorder can have poor feeding, poor weight gain, seizures, developmental delay and intellectual disability, a blood problem that results in very large red blood cells, and weak muscles. [geneaware.clinical.bcm.edu]

• Poor Growth

  71 2 0.100 0 CUI: C0878787 Disease: Growth failure Growth failure phenotype Disease or Syndrome 211 3 0.100 0 CUI: C1837385 Disease: Poor growth Poor growth phenotype Finding 167 0.100 0 CUI: C1848556 Disease: Decreased adenosylcobalamin Decreased adenosylcobalamin [disgenet.org]

  Clinical features include feeding difficulties, poor growth, hypotonia, lethargy, anemia, and developmental delay. [malacards.org]

  The patient had feeding difficulties, poor growth, hypotonia, and developmental delay. [findzebra.com]

  Early treatment also helps prevent and limit other symptoms which include: poor growth balance and coordination problems seizures immune system problems kidney problems vision loss learning delay intellectual disability [newbornscreening.on.ca]

• Fever

  TAKAYASU ARTERITIS Is also known as young female arteritis|aortic arch syndrome|pulseless disease Related symptoms: Seizures Muscle weakness Anemia Hypertension Fever SOURCES: ORPHANET OMIM MENDELIAN More info about TAKAYASU ARTERITIS Medium match ACUTE [mendelian.co]

  The patient had no relevant medical history and did not follow a specific diet, and was admitted due to fever of 38.5°C, sudden-onset confusional symptoms, disorientation in time and space, incoherent but non-dysarthric speech, and psychomotor delay. [elsevier.es]

  In order to prevent problems, call your doctor right away when your child has any of the following: loss of appetite vomiting diarrhea infection or illness fever When ill, your child needs extra fluids and carbohydrates to prevent more serious health [checkorphan.org]

  If your baby has Cbl C, D, F, you might notice signs including: Delayed growth Small head size Skin rash Vomiting Poor appetite Diarrhea Fever Sleeping longer or more often Tiredness Weak muscle tone (called hypotonia) Many of these signs may occur when [babysfirsttest.org]

• Coarctation of the Aorta

  He also had some cardiac abnormalities, including atrial septal defect, coarctation of the aorta, enlarged right ventricle, and pulmonary hypertension. The patient had an episode of neutropenia later in childhood. [findzebra.com]

  Coarctation of aorta MedGen UID: 1617 •Concept ID: C0003492 • Congenital Abnormality Coarctation of the aorta is a narrowing or constriction of a segment of the aorta. [ncbi.nlm.nih.gov]

• Recurrent Infection

  Symptoms In most children, the disease is diagnosed in the middle of an episode of metabolic decompensation. [18] Vomiting, dehydration, lethargy, seizures, recurrent infections, and progressive encephalopathy are some features of methylmalonic acidemia [emedicine.medscape.com]

• Tachypnea

  The second child, of European origin, had increased temperature and tachypnea at birth. The patient had feeding difficulties, poor growth, hypotonia, and developmental delay. [findzebra.com]

  […] system Bell-shaped thorax Delayed skeletal maturation Horizontal ribs Hypotonia Inguinal hernia Micrognathia Abnormality of the nervous system Abnormal posturing Cerebral atrophy Global developmental delay Lethargy Abnormality of the respiratory system Tachypnea [ncbi.nlm.nih.gov]

  […] levels 0002156 Hyperhomocystinemia Elevated blood homocystine 0002160 Inguinal hernia 0000023 Lethargy 0001254 Methylmalonic acidemia 0002912 Methylmalonic aciduria 0012120 Neutropenia Low blood neutrophil count Low neutrophil count [ more ] 0001875 Tachypnea [rarediseases.info.nih.gov]

  […] neurological deficits described in HMMAJ patients is less broad than that reported for individuals suffering from other forms of homocystinuria with methylmalonic acidemia and is limited to lethargy, anomalies of muscle tone, respiratory distress and tachypnea [symptoma.com]

• Dermatitis

  […] levels in the blood Elevated ketone levels in the urine Neutropenia and thrombocytopenia Elevated glycine, methylmalonic acid, and methylcitric acid levels in the blood and urine In addition to the above, if not treated promptly, patients may experience: Dermatitis [medicalhomeportal.org]

  […] impairment Red urine Pulmonary embolism Skin ulcer Ascending tubular aorta aneurysm Arterial stenosis Abnormal pattern of respiration Inflammatory abnormality of the eye Abnormal aortic valve morphology Gangrene Abnormal heart valve morphology Psoriasiform dermatitis [mendelian.co]

• Myopathy

  Sykut-Cegielska J 30281517 2018 25 Frequency of inborn errors of metabolism screening for children with unexplained acute encephalopathy at an emergency department. 38 Abdel Maksoud M...Sherif AM 29988750 2018 26 Heterogeneous Phenotypes in Lipid Storage Myopathy [malacards.org]

  Stickler syndrome, type V,614284 COL9A269.70.980.91{Intervertebral disc disease, susceptibility to},603932 COL9A373.80.960.88Epiphyseal dysplasia, multiple, 3 with or without myopathy,600969 COL9A373.80.960.88{Intervertebral disc disease, susceptibility [qgenomics.com]

  Brain atrophy Polyneuropathy Retinal dystrophy Peripheral axonal neuropathy Dilated cardiomyopathy Abnormality of the liver Multiple lipomas Hypoglycemia Jaundice Elevated serum creatine phosphokinase Visual loss Abnormality of metabolism/homeostasis Myopathy [mendelian.co]

  […] and inclusion body myopathy 2 BibTex 2015-04-30 R-HSA-4085023 Defective GFPT1 causes CMSTA1 BibTex 2014-01-08 R-HSA-4085001 Sialic acid metabolism BibTex 2014-10-31 R-HSA-4793950 Defective MAN1B1 causes MRT15 BibTex 2014-10-31 R-HSA-4793954 Defective [reactome.org]

• Muscle Hypotonia

  hypotonia, hepatomegaly and coma. [malacards.org]

• Ankylosis

  NFKBIA117.70.980.94Ectodermal dysplasia, anhidrotic, with T-cell immunodeficiency,612132 NIPBL129.30.960.94Cornelia de Lange syndrome 1122470 NOG195.210.99Brachydactyly, type B2,611377 NOG195.210.99Multiple synostoses syndrome 1186500 NOG195.210.99Stapes ankylosis [qgenomics.com]

• Peripheral Neuropathy

  Elderly patients may present with peripheral neuropathy, ataxia, loss of position and vibration senses, memory impairment, depression, and dementia in the absence of anemia. [clinlabnavigator.com]

  Exotropia Peripheral demyelination Brain atrophy Polyneuropathy Retinal dystrophy Peripheral axonal neuropathy Dilated cardiomyopathy Abnormality of the liver Multiple lipomas Hypoglycemia Jaundice Elevated serum creatine phosphokinase Visual loss Abnormality [mendelian.co]

  neuropathy (ACCPN) BibTex 2015-08-04 R-HSA-5619035 Defective SLC17A5 causes Salla disease (SD) and ISSD BibTex 2015-08-04 R-HSA-5619061 Defective SLC33A1 causes spastic paraplegia 42 (SPG42) BibTex 2015-08-04 R-HSA-5619060 Defective CP causes aceruloplasminemia [reactome.org]

• Posture Abnormal

  posture Abnormal posture phenotype Finding 4 0.100 0 [disgenet.org]

Clinical findings are non-specific and little is known about the results of diagnostic imaging to be expected in HMMAJ patients. Cerebral atrophy, a common finding in those suffering from related disorders, has been reported once [2]. Analyses of blood and urine samples have to be carried out and provide essential information as to the underlying metabolic disorder [4]:

• With regard to blood counts, megaloblastic anemia is the most common finding but micro- or normocytic anemia, leukopenia and thrombocytopenia have also been observed [3] [4].
• Hyperhomocysteinemia, hypomethioninemia, and homocystinuria are common findings in blood chemistry and urine analysis and point at a remethylation disorder. However, serum levels of methionine may also be in the lower reference range [3] [4]. Concentrations of methylmalonic acid are elevated in serum and urine samples.

Still, these results don't allow for a reliable diagnosis of HMMAJ since similar findings may be obtained in patients suffering from much more common disorders like vitamin B12 deficiency and folic acid deficiency, and in those with other hereditary diseases [5]. Serum levels of vitamin B12 and folic acid can be assessed easily, and they are not usually altered in patients suffering from homocystinuria with methylmalonic acidemia [4] [5]. However, decreased serum concentrations of vitamin B12 have been reported in isolated cases of HMMAJ [3]. In any case, the confirmation and differential diagnosis of HMMAJ require genetic and possibly complementation studies [4]. In this context, the identification of the underlying mutation is the most reliable way to confirm a tentative diagnosis of HMMAJ, and it also provides the necessary information for a familial workup and prenatal diagnosis.

Enzyme activity measurements in fibroblasts or lymphocytes constitute an alternative approach to the diagnosis of combined disorders of cobalamin metabolism, but are more cumbersome than genetic studies and don't provide any information as to the specific mutation. Nevertheless, such assays have to be carried out if the aforementioned analyses don't yield conclusive results despite strong suspicion, or if they are not available. Both methionine synthase and methylmalonyl-CoA mutase activities are decreased in case of HMMAJ.

• Neutropenia

  The patient had an episode of neutropenia later in childhood. [findzebra.com]

  […] hypertension Abnormality of the digestive system Feeding difficulties Gastroesophageal reflux Abnormality of the eye Hypertelorism Abnormality of the genitourinary system Cryptorchidism Homocystinuria Methylmalonic aciduria Abnormality of the immune system Neutropenia [ncbi.nlm.nih.gov]

  […] dyserythropoietic anemia Congenital dyserythropoietic anemia type I Congenital dyserythropoietic anemia type III Congenital dyserythropoietic anemia type II Congenital dyserythropoietic anemia type IV X-linked dyserythropoetic anemia with abnormal platelets and neutropenia [eurobloodnet.eu]

  […] growth Retarded growth [ more ] 0001510 Homocystinuria High urine homocystine levels 0002156 Hyperhomocystinemia Elevated blood homocystine 0002160 Inguinal hernia 0000023 Lethargy 0001254 Methylmalonic acidemia 0002912 Methylmalonic aciduria 0012120 Neutropenia [rarediseases.info.nih.gov]

• Neutrophil Count Decreased

  count decreased Neutrophil count decreased phenotype Finding 71 2 0.100 0 CUI: C0878787 Disease: Growth failure Growth failure phenotype Disease or Syndrome 211 3 0.100 0 CUI: C1837385 Disease: Poor growth Poor growth phenotype Finding 167 0.100 0 CUI [disgenet.org]

Guidelines for the diagnosis and management of cobalamin-related disorders including HMMAJ have recently been published [5]. In general, treatment aims at improving clinical features and normalizing hematological and metabolic values:

• Cobalamin supplementation is the mainstay of therapy. Although the administration of methylcobalamin has been reported to improve HMMAJ-associated symptoms [3], the general recommendation is to manage HMMAJ like other forms of homocystinuria with methylmalonic acidemia. In order to maintain methionine synthase activity, affected individuals should receive regular intramuscular injections of hydroxycobalamin. While the drug may also be administered via the subcutaneous or intravenous route, the efficacy of subcutaneous applications seems to be limited and long-term intravenous treatment is inconvenient. Initially, 0.33 mg of hydroxycobalamin should be administered per kg body weight and day. Over the course of the disease, single doses and injection frequencies may be lowered if clinical and laboratory parameters remain stable. In order to prevent irreversible damage to the nervous system, hydroxycobalamin should be administered to all patients presenting symptoms consistent with a remethylation disorder and those who tested positive for hyperhomocysteinemia [5].
• The administration of folate and betaine has been reported to improve disease control in patients affected by related disorders and is thus recommended as an additional therapeutic measure [4] [5]. Both folate and betaine enhance the conversion of homocysteine to methionine and thus contribute to the reduction of hyperhomocysteinemia. Beyond that, carnitine and methionine supplementation may be considered but data regarding the efficacy of this measure are scarce.
• Patients should be recommended to avoid protein restriction and circumstances that may induce a catabolic state. Nitrous oxide shouldn't be utilized in these patients either.

Although cobalamin supplementation is likely to improve neurological parameters like cognitive performance and motor function, central nervous system damage is largely irreversible. Substantial improvements in cerebral atrophy and white matter changes are not to be expected. Therefore, patients who are diagnosed and treated early have a much better prognosis than those who are diagnosed after the manifestation of clinical symptoms. In an ideal scenario, affected individuals are diagnosed before birth or identified by means of newborn screening [8]. Still, even adequate therapy cannot entirely prevent the development of HMMAJ complications and pre-existing complications may not respond to treatment. In sum, data regarding the long-term outcome of HMMAJ patients is scarce but it can be assumed that most of them will experience some degree of disability over the course of their life.

HMMAJ is caused by mutations in the ABCD4 gene [1]. This gene has also been referred to as PXMP1L, is located on long arm of chromosome 14 and encodes an ATP-binding cassette transporter initially thought to locate to the peroxisomal membrane, but more recently shown to colocalize with lysosomal proteins LAMP1 and LMBD1. Colocalization with LMBD1 is of particular interest since dysfunctional LMBD1 has been shown to trigger homocystinuria with methylmalonic acidemia type cblF [1] [9]. Both proteins may actually interact with each other [2]. In patients suffering from homocystinuria with methylmalonic acidemia type cblF, the release of cobalamin from the lysosome to the cytosol is disturbed and cobalamin is trapped inside the lysosome. It has thus been speculated that HMMAJ may be induced in a similar manner [4] [5]. However, experimental evidence has not yet been provided to this end.

Available data don't suffice to establish reliable genotype-phenotype correlations [4] [5]. However, ABCD4 mutation c.423C>G has been shown to give rise to a milder phenotype in two cases [3] [7].

Inborn errors of cobalamin metabolism are rare diseases, with HMMAJ being the least common one. Only a handful of patients have been described to date and ABCD4 mutations account for <1% of all cases of homocystinuria with methylmalonic acidemia [1] [2] [3] [4] [7]. Both males and females may be affected by HMMAJ. First symptoms usually manifest in the neonatal period or infancy, but symptom onset may be delayed until adolescence [1] [3].

HMMAJ is a combined disorder of cobalamin metabolism, i.e., the underlying mutation interferes with the synthesis of methylcobalamin and adenosylcobalamin, cofactors of methionine synthase and methylmalonyl-CoA mutase [4]. Thus, there are two pathophysiological cascades implicated in neurodegeneration and extraneural disease progression:

• Under physiological conditions, methionine synthase catalyzes the conversion of homocysteine to methionine. Functional methionine synthase deficiency is thus associated with increased serum and tissue levels of homocysteine. Homocysteine and its metabolic product homocysteic acid possibly exert neurotoxic effects and cause neurological deficits in HMMAJ patients. At the same time, methionine concentrations are reduced. Shortage of this essential amino acid may interfere with a variety of biological processes, e.g., the function of rapidly proliferating tissues such as bone marrow or epithelia. Methionine is converted to S-adenosylmethionine, which acts as a methyl group donor. Therefore, deficiencies of methionine result in a lack of S-adenosylmethionine and a decreased methylation capacity [5].
• Little is known about the contribution of functional methylmalonyl-CoA mutase deficiency to the biochemical and clinical presentation of HMMAJ. The enzyme is required for the isomerization of methylmalonyl-CoA to succinyl-CoA, which is an intermediate in the tricarboxylic acid cycle. Methylmalonyl-CoA is synthesized from propionyl-CoA. Accordingly, HMMAJ is associated with increased levels of propionyl-CoA and methylmalonyl-CoA, and decreased levels of succinyl-CoA. These conditions may affect a myriad of metabolic processes. Possibly, methylmalonyl-CoA mutase deficiency renders HMMAJ patients susceptible to metabolic decompensation [4].

It could not yet be clarified whether methionine synthase or methylmalonyl-CoA mutase fulfill non-enzymatic functions. If this was the case, the dysregulation of the respective processes would constitute another pathogenetic mechanism in HMMAJ and related disorders.

The prenatal diagnosis of HMMAJ is feasible. Mutations in the ABCD4 gene can be identified in nucleic acids isolated from chorionic villi or amniotic fluid samples. Targeted genetic analyses require strong suspicion based on the carrier state of both parents. Most reliable results are obtained if the specific ABCD4 mutations of a child's mother and father are known. If genetic studies cannot be realized or yield inconclusive results, biochemical assays and enzyme activity measurements may be carried out. In this context, increased concentrations of homocysteine and methylmalonic acid in cell-free amniotic fluid indicate the possibility of homocystinuria with methylmalonic acidemia but don't allow for the identification of its type [5].

Of note, prenatal therapy via maternal treatment with hydroxycobalamin has yielded promising results in a child affected by homocystinuria with methylmalonic acidemia type cblC and may be considered if HMMAJ is diagnosed [10].

There are four types of homocystinuria with methylmalonic acidemia, namely cblC, cblD, cblF, and cblJ [4]. All of them are induced by functional deficiencies of methionine synthase and methylmalonyl-CoA mutase, and they resemble each other in their clinical presentation. However, they differ in how enzyme deficiencies are caused. With regard to type cblJ or HMMAJ, this form of homocystinuria with methylmalonic acidemia is the result of mutations in the ABCD4 gene. The ABCD4 gene encodes a lysosomal membrane protein and pathogenic mutations result in the accumulation of unmetabolized free cobalamin in lysosomes [1] [3]. Because cobalamin export to the cytoplasm is a prerequisite for the synthesis of methylcobalamin and adenosylcobalamin, which function as cofactors for methionine synthase and methylmalonyl-CoA mutase, this condition induces functional enzyme deficiencies.

The term "homocystinuria" refers an increased excretion of homocystine in the urine. This condition may be due to distinct metabolic disorders associated with elevated serum concentrations of homocysteine, an intermediate amino acid and precursor of methionine. In patients suffering from inherited conditions that interfere with the conversion of homocysteine to methionine, blood and tissue levels of homocysteine are increased while methionine concentrations are below reference ranges.

There are different types of homocystinuria and they differ with regards to hematological and biochemical anomalies. Besides hyperhomocysteinemia and hypomethioninemia, patients may have increased serum levels of methylmalonic acids, which is why "homocystinuria with methylmalonic acidemia" is differentiated from "homocystinuria without methylmalonic aciduria". These differences originate from distinct gene defects, but they aren't reflected in the clinical presentation. Most patients suffering from homocystinuria with methylmalonic acidemia present within the neonatal period or infancy: Their parents may claim feeding difficulties and failure to thrive, and affected children show neurological deficits including, but not limited to, lethargy, anomalies of muscle tone and seizures. Occasionally, symptom onset is delayed until adolescence.

Individuals affected by homocystinuria with methylmalonic acidemia type cblJ carry mutations in a gene named ABCD4. Thus, genetic studies can be carried out to confirm the diagnosis. Genetic studies may even be realized before birth if a child's parents are known to be carriers of ABCD4 mutations. Children will develop the disease if they inherit pathogenic alleles from their mother and their father. Only a handful of cases have been described to date, so recommendations regarding diagnosis and treatment are mainly based on experiences with patients suffering from other forms of homocystinuria with methylmalonic acidemia. In this context, it is likely that the patients' prognosis largely depends on the time of diagnosis and initiation of treatment. The earlier an adequate treatment is started, the better the prognosis of the individual patient. Treatment consists in intramuscular injections of hydroxycobalamin and oral supplementation of betaine and folic acid. Lifelong therapy is required in all cases and despite utmost compliance with therapeutic regimens, it may not be possible to prevent all complications. If left untreated, homocystinuria with methylmalonic acidemia type cblF follows a slowly progressive course and may lead to severe disability or death.

1. Coelho D, Kim JC, Miousse IR, et al. Mutations in ABCD4 cause a new inborn error of vitamin B12 metabolism. Nat Genet. 2012; 44(10):1152-1155.
2. Fettelschoss V, Burda P, Sagné C, et al. Clinical or ATPase domain mutations in ABCD4 disrupt the interaction between the vitamin B12-trafficking proteins ABCD4 and LMBD1. J Biol Chem. 2017; 292(28):11980-11991.
3. Kim JC, Lee NC, Hwu PW, et al. Late onset of symptoms in an atypical patient with the cblJ inborn error of vitamin B12 metabolism: diagnosis and novel mutation revealed by exome sequencing. Mol Genet Metab. 2012; 107(4):664-668.
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5. Huemer M, Diodato D, Schwahn B, et al. Guidelines for diagnosis and management of the cobalamin-related remethylation disorders cblC, cblD, cblE, cblF, cblG, cblJ and MTHFR deficiency. J Inherit Metab Dis. 2017; 40(1):21-48.
6. Morath MA, Hörster F, Sauer SW. Renal dysfunction in methylmalonic acidurias: review for the pediatric nephrologist. Pediatr Nephrol. 2013; 28(2):227-235.
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9. Rutsch F, Gailus S, Miousse IR, et al. Identification of a putative lysosomal cobalamin exporter altered in the cblF defect of vitamin B12 metabolism. Nat Genet. 2009; 41(2):234-239.
10. Trefz FK, Scheible D, Frauendienst-Egger G, et al. Successful intrauterine treatment of a patient with cobalamin C defect. Mol Genet Metab Rep. 2016; 6:55-59.