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THE JUVENILE FORM OF METACHROMATIC LEUKODYSTROPHY (MLD): THE CASE OF TWIN GIRLS
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Metachromatic leukodystrophy (MLD) is a rare neurometabolic disease caused by the deficiency of the lysosomal enzyme arylsulfatase A (ARSA) activity. The absence or deficiency of arylsulfatase A leads to accumulation of cerebroside sulfate within the myelin of the central nervous system (CNS) and the peripheral nervous system (PNS). This in turn, causes the CNS and PNS to progressively deteriorate leading to both features of central and peripheric motor neuron dysfunctions. The clinical features of brain dysfunction like gait disturbance, speech, hearing and visual problems appear gradually, become progressive and fatal over time. Our 10 years old patients, who were developmentally normal, until 4 month ago, show psychomotor restlessness, anxious mood, bizarre behavior, imediat and delayed echolalia, school setback, mixed enuresis, symptoms which gradually increased. Although the symptoms within the hospitalization period advocated for a psychiatric disorder, the neurological, biologic and imaging investigation of each case is very important; multidisciplinary approach led to a full diagnosis. The results of their investigations were suggestive of metachromatic leukodystrophy. Symptomatic treatment and adequate counseling concerning the disorder and its prognosis, as well as psychological support were done.
Metachromatic leukodystrophy (MLD) is an autosomal recessive neurodegenerative disease, characterized by the lack of arylsulfatase A.
This leads to the accumulation of sulfated glycolipids in the nervous system myelin sheaths and to a lesser extent, in the visceral organs such as the liver, the gall bladder and the kidneys.
In the nervous central system, this accumulation has the progressive de-myelinization as result . Metachromatic leukodystrophy is named after how cells accumulating sulphatides, appear when viewed under a microscope.
Metachromatic leukodystrophy is divided into three clinical subtypes depending on the age of onset: infantile, juvenile and adult form [2, 3].
The impact of the genetic and environmental factors is not yet well understood. We describe the case of monozygotic twins with juvenile-onset metachromatic leukodystrophy, which share a common environment, the same genetic mutations that demonstrated a remarkable synchronicity in the neuropsychiatric decline.
We present the case of twin sisters aged 10 years and 3 months (RS and VS) residents of rural areas, at the first hospitalization in the Psychiatry and Neurology for Children and Adolescents Clinic Timişoara, brought by the mother for psychomotor restlessness states, anxious mood, bizarre behavior, delayed echolalia, school setback and mixed enuresis, which have appeared after a psychotrauma.
Personal history: they are coming from twin pregnancy, born at 8 months. Neuro-psychological development according to the appropriate age stages until 4 months ago; they were vaccinated according to the MH scheme.
Family history: not significant, no data is known about their father.
Life conditions: patients live with their grandparents and the maternal uncle in modest conditions; the father left the family when the mother got pregnant. The family relationships are strained: the uncle is an alchoolic, being verbally and physically aggressive; the mother is working abroad and is visiting her daughters during holidays.
The patients attend school from the age of 7 with satisfactory results until the autumn of 2015, when the teacher draws attention to the cognitive decline and the changes of their behaviour.
From their history we note that their symptoms started with psychomotor restlessness states, mood anxiety, bizarre behavior, immediate and delayed echolalia, school regress, mixed enuresis and affirmative the symptoms started a month before the hospitalization, after witnessing a psychotraumatic event (the maternal uncle produced himself lesions by cutting his teguments).
Objective Exam: cardiopulmonary balanced; soft and elastic abdomen, mobile respiratory movements, spontaneous and painless on palpation; free renal lodges, present diuresis.
Neurological examination: standing and walking possible; evidence of coordination can not be made (patients do not understand verbal commands); osteo-tendinous hyporeflexia; bilateral Babinski in flexion; no signs of meningeal irritation; CN -I-XII pairs in normal relations;
Psychiatric examination patient RS:
Patient with accurate carriage, hyperexpression facies, facial grimacing, uninhibited attitude; Temporo-spatial oriented auto and allo-psychic;
Field of clear consciousness; The psychic contact relatively easily achieved, maintaining eye contact during the interview but of short duration;
Concentration and persistence hypoprosexia de concentrare și persistență; Prolonged attention spans during self-initiated activity; Impaired in broadening the spatial spread of visual attention.
Lack of concentration.
Without any pathologic signs in the area of perception in the moment of examination.
Oversensitivity to stimuli alternates with periods of non-responsiveness.
Expressive language developed below chronological age, speech and expressive language difficulties, ideo-verbal incoerence jumping from one idea to another, until echolalia is noticed.
Language disturbance are evidenced: regression of language skills, inadequate comprehension of speech.
The comprehension of discourse is more impaired than the expression giving the aspect of mixed receptive/expressive language deficit.
Language processing deficits are evident – production of overlearned scripts and perseveration by incessant repetitive questioning.
The aspect of verbal auditory agnosia (VAA) is created by the inability to decode the speech presented to the auditory channel with relative preserved ability to decode language presented to the visual channel posibil caused by the temporal lobe dysfunction. The semantic processing in both production and comprehension relies on specialized regions within the temporal lobe and the frontal areas; the left temporal damage being a predictor of delayed language production some – what later in development.
Immediate echolalia or delayed perseveration, abnormal prosody, syntax, semantics and pragmatics and speech articulation deficit (aphemia) – a disruption in the patient’s voluntary speech production ability and recurring utterances such as “tan tan tan”; “yes, yes”, can be observed.
This symptom is not associated with the injury of a specific cortical area, but with damage to the left superior arcuate fasciculus passing from the temporal lobe over the lateral ventricle to the anterior regions.
The regression of graphomotor skills is observed; the writing is disorganised, alexia is noticed.
Marked emotional lability from euphoria to psychomotor agitation, disinhibited behavior, comportament dezinhibat, laughing without motivation, temper tantrums; Impaired social communication.
She presents stereotyped behaviors and activities. Toys are handled bizarrely.
Decreased initiation of voluntary movements. Markedly impaired creativity. Manierisms: repetitive, stereotyped movements such as hand flapping.Episodes of hyperactivity, disorganized, without any purpose, which oscillate with indifference.
Cognitive and behavioral rigidity and repetitive behaviors.Deficits on problem-solving tasks.
Partial self-serving behaviour; she needs help for personal hygiene and putting on the clothes, for going down the stairs. Appetite partialy keeped with some difficulties when eating solid;
Impaired social skills, and insight into other thinking. Insomnia, ameliorated after introducing the treatment.
Psychiatric examination patient VS :
The psychiatric exam puts into light the same regression of language skills, mixed receptive/expressive dysfluent language deficit, impaired social communication, regression in neuropsychological abilities, cognitive and behavioral rigidity and repetitive behaviors, echolalia and inadequate prosodia.
In comparison with RS, VS shows episodes of tendency for isolation, intolerance of people in close proximity and a preserved capacity in their ability to use expressive language, but her speech is monotonous with an impaired prosodic intonation; tendency to use telegraphic language, often structured in the form of simple noun/verb sentences that frequently omitted grammatical elements and often included uninflected verbs.
Changes in social behavior are discretely moderated in comparison with those noted at her twin sister.
The case history, the physical examination, the neurologic and the psychiatric exam oriented us for the stage diagnosis (of probability):
Childhood disintegrative disorder, according to DSM IV diagnostic criteria :
- Patients had a normal course development in the early years after birth, communicated verbally and non-verbally, had age-appropriate play and behavior
- There was a loss of earlier acquisitions (before the age of 10 years) in terms of expressive and receptive language, sphincter control, adaptive behavior and social attitudes, game
- Qualitative deterioration of social interaction, of expressive language and motor mannerisms occurred
- Criteria of Pervasive Developmental Disorder or Schizophrenia are not met
For the accurate diagnosis, the following targeted complementary explorations were made:
Hemo-leucogram, transaminases, urea, creatinine, blood glucose, urine exam - normal relations
patient RS: Monomorphic theta rhythms. Series of subclinical unsystematised generalized poly-spike wave paroxysms.
patient VS: Monomorphic theta rhythms. Asymmetries with a discrete interemisheric asymmetry and generalized Sharp and Waves spikes
Eye consult: - normal aspect (both patients)
Psychological examination patient RS: IQ <33 Binet-Simon
The patient got up from the chair, jumps, speaks in echo, is repeating stereotyped “Yes! Yes!”; presents a repeated gesture with her lips, a disorganized behavior; when put to count without jumping from the seat, she succeeds only till 20.
She also has brief moments during which the tone of her voice is normal and she is answering a simple task without being analytical.
Psychological examination patient VS:
VIQ = 60, PIQ = 35, IQ = 43 WISC
The patient experiences sudden swings in behavior, pampered speech, echolalia. Drawing is significantly degraded. L. Bender: retardation / marked setback; organic structure indices. Sometimes she cannot respond to simple tasks (eg how many legs has a dog? 10) but gives correct answers to more complex tasks (ie what resembles plum and peach? Fruits) She writes a few words dictation, but there is a dis-graphic, disorganized appearance.
At this stage, we considered the diagnoses on axes:
Childhood Disintegrative Disorder
Medium Mental Retardation QI=43 WISC (patient VS) and Severe Mental Retardation QI=33 B. Simon (patient RS)
Problems with the primary support network
GAF= 55 (patient VS); GAF=40 (patient RS)
Stage Differential Diagnosis:
In the the first stage of diagnosis, we sustained the diagnosis of Childhood Disintegrative Disorder, differentiating it from the other pervasive developmental disorders by the fact that the onset was after the age of 9 and the evolution was progredient, unlike the autistic spectrum disorder and the Asperger disorder where previous aquisitions are not lost and the psychomotor progress can be done .
We excluded the Rett syndrome presenting neurologic impairment also, based on the trunk ataxia and the loss of hand apprehensiveness function and the earlier onset of the Rett syndrome.The Rett syndrome is a disorder, characteristically observed in girls, being associated with some different mutations of the protein of the gene which codes Methyl-CPG-Protein2 of binding (MeCP2). Mutations have been discovered in the variants of Rett syndrome in the case of boys with mental retardation and occasionally in children with autism, too.
Because there are several atypical cases along a broad spectrum of clinical manifestations- because of the variable clinical severity, probably reflecting the type and locus of the MeCP2 genetic mutation, associated to the possible variability of the X chromosome inactivation – the Rett syndrome should be always taken into account during the differential diagnosis with any kind of cognitive regression, especially in the cases of girls with autism (Shanen et al, 2004) .
We also excluded Multiple Complex Developmental Disorder (MCDD), a similar entity with ASD (autism spectrum disorder), described by Cohen, which differs from ASD by the clinical and behavioral characteristics (Buitelaar, Van der Gaag, 1998).
This, in DSM IV or ICD-10, not included entity, means the exclusion of the diagnosis of autism or VEOS (Very Early Onset Schizophrenia) and includes fears, unusual phobias, episodes of disorganized behavior, along with the impairment of the social behavior and a severe disruption of attachment, with the onset around the age of 5 [4,6].
The autistic-like symptoms were also excluded: mental retardation, with impaired social interaction and stereotyped movements and the hyperactivity associated with mental retardation and stereotyped movements (ICD 10), patients having a life history of normal development until the age of 9  .
A great deal of linguistic research has been devoted to the study of the semantic-pragmatic language disorder and its associated deficits on receptive language disorders in autism (Tager-Flusberg, 2003) and a study of electrophysiologic correlates of semantic deficits in intelligent children with autism (Dunn, Bates, 2004).
It is important to mention here that there are children who undergo a catastrophic autistic regression (disintegrative disorder) at preschoolers or at school-age; although the disintegrative disorder is generally stated to have a worse outcome than autism (Volkmar, Cohen, 1989) .
In comparison to children with autistic regression, those with disintegrative disorder of childhood more often show fearfulness during the period of speech loss, and more commonly show stereotypies after speech loss and a significantly uneven intellectual profile (Kurita et al, 2004) . The risk of epilepsy is as high as 70 per cent (Mouridsen et al, 1999) .
In disintegrative disorder of childhood, regression is more profound, with a general cognitive regression.
In the frame of developmental language disorders, regression is not typical for the most cases, the language regression may occur as the worsening of already abnormally developing language in some cases (Tuchman, Klein et al, 2000) without any evidence of bioelectric abnormality suggestive of a known disorder or any other apparent cause.
In the frame of developmental language disorders, the verbal auditory agnosia language expression and reception are generally disordered. A genetic susceptibility to language disorders is indicated by the aggregation of cases within extended families and their co-occurrence in monozygotic twins. A common genetic basis for motor immaturity and DLD has been suggested. An abnormal gene, FOXP2 on chromosome 7q31, is associated with dyspraxic speech.
Based on the the life history: the absence of the appropriate maternal care of a possible emotional deprivation and the tensioned nonstimulative family environment, along with an adhesive non-discriminatory behavior (embraces of staff), the regressive behavior, but that briefly appeared around the age of 10 we also excluded the diagnosis of Reactive Attachment Disorder.
Since the patients were brought for a change in social behavior and the regression occurred in connection with a psycho-trauma, it was necessary to exclude a reactive cause, which can cause cognitive regression and transient language regression and mental functioning fluctuations, but these are improved through the removal from the environment, psychotherapy and medication administration.
Psychiatric and psychological causes – severe emotional disturbance, selective mutism, due to difficult life events or disasters may cause transient, episodic cognitive/language regression, or fluctuations in the mental functions. Selective mutism can be easily differentiated from other disorders that cause language regression on the basis of typical clinical features and the absence of EEG and other laboratory findings.
The parents tend to attribute the regression to environmental causes, like in the case of our patients, the twins for whom the cognitive regression was correlated with a psycho-traumatic event.
Epileptiform activities in the EEG are also seen in some children with developmental dysphasia (Picard et al, 1998), adding difficulties to the differential diagnosis of Landau-Keffner syndrome and related disorders. The Landau-Kleffner syndrome (aphasia with epilepsy) was excluded, because of the fact that our patients didn’t show epileptic features.
Other neurological conditions with cognitive/language deterioration of children may be a feature of many progressive degenerative neurologic disorders such as leucodystrophies, subacute sclerosing, panencephalitis (SSPE), Wilson’s disease and Huntington’s Chorea.
Finally, a progressive hearing loss acquired during the critical stages of language acquisition, may give rise to language regression for acquired deafness may need to be considered.
Language regression is the loss of previously acquired language abilities affecting comprehension, expression or both, and is usually accompanied by cognitive deterioration after normal or near normal neurological and mental development.
Isolated language regression, except in Landau-Kleffner syndrome or acquired epileptic aphasia is rare. Language regression occurs commonly within the context of autism or of a more generalized cognitive regression in many different disorders of childhood, with or without epilepsy or epileptiform discharges on EEG (in one third of cases in LKS there is no history of seizures and it starts as late as 10-12 years and it is accompanied by language regression, hyperactivity, temper tantrums, aggressiveness or impaired social communication).
Landau-Kleffner Syndrom (LKS) and some other epileptic disorders characterized by electro-clinical status epilepticus during slow sleep (ESES), autistic regression and disintegrative disorder of childhood, and developmental language disorders should specifically be included in the differential diagnosis of language or cognitive regression.
Neurological disorders characterized by language/cognitive deterioration (Rogers, 2004) appear in: critical epileptiform discharges with or without epilepsy (Transient cognitive impairment, Non-convulsive status epilepticus, Epileptic syndromes with cognitive (language) autistic regression and EEG abnormalities – LKS, continuous spike and wave during slow sleep (CSWS). Pervasive developmental disorder (Autistic regression, Rett syndrome, Disintegrative disorder); Developmental language disorders; other neurological causes including dementia of childhood : SSPE, Wilson’s disease, leuko-dystrophies and psychiatric and psychological causes.
Although most of these disorders have distinctive features, they have many overlapping clinical and laboratory findings, and one disorder may evolve into another over time (McVicar, Shinnar, 2004) [10, 11].
Indeed, different syndromes and clinical disorders result from the involvement of different brain regions with diverse etiologies, although they share common pathogenic mechanism.
Recent research underlines that disintegrative disorder would actually be a metabolic yet unidentified disease [4, 12].
Due to this reason, they have continued further investigations, especially since the evolution during hospitalization was degrading, reason for which the brain MRI was done.
The brain MRI revealed at patient VS: T2 hyper demyelinating lesions in the periventricular white substance of the whole aspect of butterfly, bilaterally symmetrical lesions in the corpus callosum extended; T2 lesions hyper track to the based pyramid in the midbrain basal nuclei and symmetric bilateral in the midbrain (Fig. 1, Fig.2).
Figure 1. Brain MRI of the patient VS
Figure 2. Brain MRI of the patient VS
The brain MRI of the patient RS showed symmetrical diffuse modifications periventricular fronto-temporo-parietal white matter - hyper-signal FLAIR; T2 with iso-linear strips that give injuries a brindle aspect; hypo-signal T1 without SDC outlet without hemosiderin changes gave by diffuse demyelination; demyelination affects partly and bilateral frontal and temporal subcortical fibers, knee and the splenium of corpus callosum, posterior arm of the internal capsula bilateral corticospinal tracts and mesencephalic: segment; DWI and ADC sequence, there are visible areas of diffusion situated to the bilateral fronto-temporo-parietal periphery corresponding to the active demyelination
(Fig. 3, Fig. 4).
Figure 3. Brain MRI of the patient RS
Figure 4. Brain MRI of the patient RS
These results through the recent degradation, raises suspicion of Subacute Sclerosing Panencephalitis or Metachromatic Leukodystrophy .
Further blood was collected and measles antibodies were dosed who had the value of : 1521 IU / ml for the patient RS and 1887 IU / ml for VS. Also cerebrospinal fluid (CSF) was collected, of which were dosed measles antibodies and the result refuted the diagnosis of Subacute Sclerosing Panencephalitis. For the diagnosis certainty, investigations like Arylsulfatase A dosing were done and the results have shown a marked decrease in both patients (Fig. 5).
Figure 5. Results of the Arylsulfatase A dosing
These results have facilitated the diagnosis orientation for Metachromatic Leukodystrophy [14, 15]. Thus, finally, anamnesis, physical examination, laboratory explorations allowed us the positive diagnosis of juvenile form of Metachromatic Leukodystrophy.
The positive diagnosis of Metachromatic Leukodystrophy is well supported by diagnostic criteria:
- neuro-psychological setback
- brain MRI
- arylsulfatase A dosage (serum and urine)
It requires a review of the the following elements:
Based on the anamnesis, which shows a relative acute onset, with relative recent changes in the mental status, the differentiation from acute disseminative encephalomyelitis is imposed, those having an infection as precursor and affect predominantly the white substance, fact that hasn’t been mentioned in the anamnesis.
There we face the problem of differentiating between the noninfectious, probably autoimmune disorders – (acute demyelinisation encephalomyeltis, Multiple Sclerosis); Inflammatory or infectious demyelinisation disorders – SSPE, Multifocal Progressive Leukoencehalites .
Early infantile Multiple Sclerosis (EIMS) with onset between 1-5 years, delayed infantile MS (DIMS) beginning between 5 and 10 yeras, and juvenile MS (JMS) beginning between 10-16 years. Cognitive impairment has been demonstrated in pediatric Multiple Sclerosis patients, but children with MS more frequently present with a polysymptomatic form of the disease then a monosymptomatic one (pyramidal syndrome, myclopathy ataxia, extrapyramidal signs, loss of vision, seizures).
Cerebro Spinal Fluid abnormalities in MS patients are characteristic: the presence in the CSF of a detectable oligoclonal immunoglobulins by electropharesis, elevated rates of immunoglobulin G (IgG) and IgM, oligoclonal bands (OCB) of IgG present in the CSF and absent in blood in 53% of children.
The MRI images observed in children with an initial attack of EIMS or DIMS recall the images of patients with ADEM (Acute disseminated encephalomyelitis).
MRI lesions must fulfill the diagnostic criteria of space dissemination in adults but children with MS appear to have fewer white matter lesions.
MRI and MR spectroscopy (MRS) in children shows brain atrophy and loss of axonal integrity.
In SSPE (Subacute Sclerosing Panencepahalitis), the mental deterioration, the myoclonic seizures, involuntary movements and characteristic EEG with Radermecker complexes, appear. In the same time the titre of measless antibodies is raised. In our case the biologic probes excluded SSPE.
We will further proceed to the differential diagnosis of hereditary myelin metabolism disorders (Adrenoleukodystrophy, Metachromatic Leukodystrophy, Multiple Sulfatase Deficiency, Krabbe disease, Alexander disease).
In the same time, on the anamnesis basis, the toxical diseases and the post hypoxic–ischemic leukoencephalopathy, have been excluded. Through the progressive character of the lesions, we must eliminate the pre- and perinatal pathology which is not progressive.
From the degenerative disorders which primary affect the white substance, we will revise :
The X linked Adrenoleukodystrophy. The cerebral form has its onset between 5-8 years, with gradual perturbation of gait/walking and cognitive deterioration, anormal pigmentation, crying and screaming attacks, spastic contractures of the inferior limbs, ataxia and high levels of fatty acids chains in the plasma (VLCFA). The genetic analyses show the ABCD 1 mutation in the Xq28 chromosome .
Alexander Disease – the juvenile form has its onset between 5-9 yers, the bulbar signs appearing invariably in the juvenil form. At the MRI the changes of the white matter are predominant in the frontal area, at the level of basal ganglia, thalamus and brain stem [17, 18].
Crabbe Disease – the juvenile form, the predominant symptoms include motor and sensorial neuropathy, spastic paraparesis and optic atrophy, and in the cerebrospinal fluid appears proteinrahia. The genetic analysis identifies the GALC gene localised on the chromosome 14. At the MRI, the lesions of the white matter are more restricted affecting the periventricular region, the calos corpus and the occipital lobes [17, 18].
The Saposin B deficiency (in the case of this disorder the sulfatides are accumulating in the nervous system, eventhough the level of the Arylsulfatase A enzyme is normal, the accumulation being due to the non- activation of the enzyme, the activation being not in a proper manner).
Other disorders which affect the cerebral white matter – The imagistic evaluations of the children with neurologic disorders and cognitive deterioration put into evidence situations, entities which can’t be captured in the described categories.
METACHROMATIC LEUKODYSTROPHY - THE JUVENILE FORM
Palliative care can help with many of the symptoms and usually improves quality of life of the patient.
There is currently no treatment or cure for MLD. Children with advanced juvenile or adult onset and late infantile patients displaying symptoms receive treatment limited to symptom management .
Pre-symptomatic late infantile MLD patients, as well as those with juvenile or adult MLD that are either pre-symptomatic or displaying mild to moderate symptoms, have the option of bone marrow transplantation (including stem cell transplantation), which is under investigation to see if it may slow down progression of the disease or stop its progression in the central nervous system .
However, results in the peripheral nervous system have been less dramatic, and the long-term results of these therapies have been mixed.
Recent success has involved stem cells being taken from the bone marrow of children with the disorder and infecting the cells with a retro-virus, replacing the stem cells mutated gene with the repaired gene before re-injecting it back into the patient where they multiplied. The children by the age of five where all in good condition and going to kindergarten when normally by this age, children with the disease cannot even speak [20, 21].
Several future treatment options are currently being investigated. These include gene therapy, enzyme replacement therapy (ERT), substrate reduction therapy (SRT), and potentially enzyme enhancement therapy (EET) [22, 23].
Bone marrow and stem cell transplant therapies:
Several trials are underway to continue to improve the effectiveness and reduce the risks of bone marrow and stem cell transplants. Cord blood transplants and reduced preparative routines are being studied.
Two different approaches to gene therapy are currently being researched for MLD.
Gene therapy with an autologous stem cell transplant and Intracerebral Gene therapy (phaseI/II clinical trials) [22, 23].
Enzyme replacement therapy (ERT)
Substrate reduction therapy:
The Cooper Health System (New Jersey) sponsored a clinical trial underway to determine the safety and efficacy of a Vitamin K antagonist (Warfarin) in treating Metachromatic Leukodystrophy (MLD) in 2009.
The treatment for the discussed patients is currently symptomatic with timostabilising effect (Neurotop R 300 mg) anxiolytic (Alprazolam) and Neurotrophic (Omega 3.6.9 and Biocebral). The objectives being to increase the quality of life of these patients. Also they were included in family and supportive therapy programs and psychological counseling.
The evolution is progressive, with the possible appearance of neurologic sequeale, of convulsive seizures, of medical complications (suprainfections).
Immediate and long-term prognosis is reserved (Fig. 6).
Figure 6. Survival Probability from the symptoms onset, in the three subtypes of Metachromatic Leukodystrophy
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