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[00:00:00] Dr. Nathalie Guffon: Hello, everyone. It's my pleasure to welcome you to this second webinar of the alpha-mannosidosis series with the title "Diagnosing Alpha-Mannosidosis in Practice". My name is Nathalie Guffon, I am responsible of the Reference Center for Inherited Metabolic Disease in Lyon in France. I am a pediatrician, but I take care of both children and adults. I am involved in alpha- mannosidosis for many years with 20 patients followed in my center. Before starting, I will give you some housekeeping. Please do not take any screenshots and do not reproduce any slides, content, or images without the express written permission of the speaker. There will be a Q& A at the end of the presentation. Questions can be only submitted by text and not verbally.
[00:01:07] Dr. Nathalie Guffon: Recorded webinars will also be available on the online AM resource center at the link you can see. So we can move to the presentation. I will start by presenting some clinical cases of patients diagnosed at different ages and then move on to a diagnostic algorithm. Just to remind you, from Dr. Martin Magner's previous presentation, that alpha- mannosidosis is a lysosomal storage disease due to alpha-mannosidase deficiency, leading to the defective degradation of glycoproteins and accumulation of mannose-rich oligosaccharides in body fluids and tissues, resulting in apoptosis and impaired cellular function. Alpha-mannosidase deficiency is caused by pathogenic variants in the MAN2B1 gene and is inherited in an autosomal recessive fashion. 1 in 500, 000 to 1 in 1 million. The question is whether it is so rare or underdiagnosed. Alpha-mannosidosis patients present with a broad heterogeneity of symptoms. Facial dysmorphia is similar to that of mucopolysaccharidosis also less marked with macrocephaly, prominent frontal arms, thick features and a short neck. It is important to underline that dysmorphism may be very discrete and even absent. In some cases there is craniosynostosis with microcephaly. In terms of central nervous system involvement, hydrocephalus is present in the most severe form.
All patients develop academic difficulties and cognitive deficits of varying severity. Behavioral disorders are common and generally after 10 years of age psychiatric disorders such as acute psychosis, hallucinations and depression appear. Almost all patients present a hearing loss with speech delay. Ophthalmological manifestations are less frequent and more delayed than in mucopolysaccharidosis. Nevertheless, strabismus and hypermetropia are common in childhood. Corneal clouding and retinopathy appear with age. Motor impairment is extremely frequent with muscular weakness, hypotonia, balance and coordination disorders, fine motor skill impairment. Balance disorders worsen leading to talk of ataxia even if there is no true cerebellar syndrome. Immunodeficiency due to immunoglobulin G deficiency explains recurrent infections. On the osteoarticular level, genu valgum is extremely common. In children, the joints are generally stiffer or even hyperlax. Whereas in adults, joint stiffness develops particularly in the shoulders and hip. Multiplex dysostosis is less prominent than in mucopolysaccharidosis. The final size is usually normal. Osteopenia or osteoporosis is common. In adulthood, the disease progresses to a destructive polyarthropathy. The cardiorespiratory system evolves slowly with valvulopathy and myocardiopathy, asthma or pseudo- asthma, respiratory insufficiency and sleep apnea. It is important to note that the phenotypic variability is high even between siblings with identical genotypes. Now, let us take a look at the clinical manifestation of alpha-manosidosis through clinical trials. The first study is a natural history study which included 45 patients: 22 children and 23 adults. This study showed that all patients suffered significant hearing loss due to both conductive and neurosensory components.
All patients presented with mental retardation. Balance disorders or ataxia were reported for 71% of children and 79% of adults. Psychotic disorders were present in 52% of patients at baseline and 79% two years later. Skeletal deformities were seen in 62% of pediatrics patients and 92% of the adults. All patients have normal height and 9 were overweight. In a second clinical trial including 33 patients, 14 children and 19 adults, 97% of the population demonstrated either impaired or seriously impaired hearing. About 64% of patients presented with a history of infection and infestations. 37. 5% of a subset of 25 patients presented impaired or seriously impaired serum immunoglobulin G levels. If we now turn to attempt at phenotype classification of alpha- mannosidosis, the most recent is that proposed by Malm. It distinguishes three phenotypes. Type 1, clinically mild form, recognized after 10 years of age, without skeletal abnormalities and with very slow progression. Type 2, more frequent, moderate form, recognized before 10 years of age, with skeletal abnormalities, slow progression and development of ataxia between the age of 20 to 30 years. Type 3 the severe form, immediately recognized with skeletal abnormalities and obvious progression resulting in early death from central nervous system involvement or myopathy. When we try to apply this classification to the 33 patients included in the clinical trial, we find that there are no type 3 and that over 45% correspond to neither type 1 or type 2, either because they have ataxia without bone abnormalities or conversely bone abnormalities without ataxia.
Most patients are classified as type 1, but 10 out of 11 of these patients have motor organ involvement, 7 are classified as type 2, but 4 out of 5 children have ataxia. The phenotypes of alpha-mannosidosis patients are therefore not considered clearly distinguishable, and predicting the clinical course of an individual patient is very challenging. I will now present you a few clinical stories of patients diagnosed with alpha- mannosidosis at different ages. The first patient is a third child from non-consanguineous parents. He is born after normal pregnancy and delivery with normal weight, height and age circumference. The neonatal clinical examination was normal, with only bilateral metatarsus varus leading to physiotherapy prescription.It presented with recurrent bilateral otitis since the first month of age, then recurrent rhinopharyngitis leading to adenoidectomy and recurrent T- tube insertion at 21 months of age. The parent reported muscular weakness compared to their other children, with difficulties holding their head and walking at 18 months of age. He presented a speech delay at 2 years of age, leading to the diagnosis of hearing loss. The parents described him as clumpsy. On clinical examination, he presented progressive macrocephaly and some coarse facial features. The gross curve showed progressive macrocephaly and accelerated growth velocity. He was first suspected for mucopolysaccharidosis, but urinary glycosaminoglycans were normal. But urinary oligosaccharides showed alpha-mannosidase deficiency profile. So diagnosis was confirmed by leukocyte enzyme deficiency and then DNA analysis. The second patient is the second child of consanguineous parents.
[00:11:55] Dr. Nathalie Guffon: The pregnancy was marked by an open cervix in the 4th month, leading to bed rest in the 5th month. Finally, she was born at 37 weeks with a normal clinical examination. The first symptoms appeared at 1. 5 months of age with umbilical hernia, then peripheral hypotonia at 5 months of age. Since the age of 5 months, she presented with chronic nasal congestion, recurrent bronchitis and bronchiolitis, and pneumopathy with hospitalization at 9, 10, and 12 months. Her left strabismus was noticed at 22 months of age, and then a mild hepatosplenomegaly. A speech delay with communication delay was reported. And at school, the teacher said to the parents that the girl has peripheral disturbance with passivity and opposition. The school asked for a psychomotor evaluation which was performed at 3. 5 years of age.
This evaluation leads to conclude to balance and coordination disturbance, slowness, fatigability, speech delay and joint laxity and finally a global psychomotor retardation with a DQ of 71. At 3 years and 10 months she was hospitalized for psychomotor delay. MRI was normal, moderate dysmorphia was noted with coarse facial features, short neck, flattened nasal bridge. Her growth curve profile showed macrocephaly over 8, she has stable hepatosplenomegaly, left strabismus with hypermetropia and astigmatia. She has skeletal abnormalities with mild dysostosis multiplex. A myelogram was performed and showed vacuolated lymphocytes. She was first screened for mucopolysaccharidosis with normal urinary glycosaminoglycans, but on oligosaccharide profile there is an alpha- mannosidosis profile. The diagnosis was also confirmed by activity deficiency and then gene analysis. The third patient is the third child of non- consanguineous parents. He has two siblings in good health, the pregnancy and delivery were normal. He presents with a normal initial development and was able to walk at 9 months and to say first word at a normal age. At two years of age, he presented with recurrent otitis media leading to the diagnosis of hypoacousia. He has also speech delay and finally a moderate neurosensorial hearing impairment was diagnosed. At three years of age, the school reported behavioral disturbance with aggressive reaction. He starts with hearing aids at 4 years of age and entering a special school for hearing deficient people at five years. At seven years he has mild mental retardation with IQ of 80. He also has dental problems, normal growth, slight over weight, normal cardiac and ophthalmologic examination. Between the age of 10 and 11, he presents always bilateral medium deafness, mild cognitive impairment with speech delay and behavioral disturbance, but also mild dysmorphia with large forehead, hypoplasia of midface, marked nasal swelling, prognathism and thin lips. He has also thick and profuse hair, infiltrated skin, joint stiffness especially shoulders, mild pectus carinatum and mild thoracolumbar kyphosis with normal x- ray. There are vacuolated lymphocytes in the blood, and urinary oligosaccharides show an alpha-mannosidosis profile. The diagnosis was confirmed by alpha-mannosidase activity deficiency and gene mutation.
The last patient has nine siblings. He was born after a normal pregnancy. The medical history started at a pediatric age with feeding difficulties at six months, normal initial development with the ability to walk at 14 months, no speech delay. At three years, the patient has surgery for craniosynostosis and was diagnosed as having a Crouzon disease. He presents with moderate mental retardation but was able to follow normal school until eight years of age, then go to a special school. She also was diagnosed during infancy with hearing impairment. Now with medical history during adulthood, she developed insulin- dependent diabetes at 22 years of age, then psychomotor regression. She was at home with no activities and at the beginning, the psychomotor regression was due to the less activity. At 34 years of age she was hospitalized because of hips and ankle pains. Radiography showed coxarthrosis, dysostasis multiplex. She also has leukopenia and thrombocytopenia. She has a myelogram and the myelogram showed vacuolar macrophages leading to the suspicion of lysosomal storage disease. She was first screened for glycosaminoglycan with a normal profile and then for oligosaccharides with alpha-mannosidosis profile. The diagnosis was confirmed by the decrease of alpha-mannosidase activity. So for this patient, the diagnosis of alpha-mannosidosis was made at 34 years of age with a clinical history since infancy. So, finally, when should alpha-mannosidosis be suspected? In an attempt to answer to this question we have in an international working group with aim of publishing a diagnostic algorithm. We use a Delphi- like method and publish two algorithms based on patient age. For children under 10, the key symptom is deafness and or speech delay. Naturally, speech delay leads to a search of signs of alpha-mannosidosis that are psychomotor retardation, motor disturbances, with balance and coordination problem, facial dysmorphia similar to mycopolysaccharidosis, but less marked. For patients older than 10 years of age, the clinical symptoms leading to consultation are intellectual disability and motor regression and or psychiatric manifestation. It is important to check the patient's medical history for things pointing to the diagnosis of alpha- menosidosis, hearing loss, intellectual disability, motor disturbance such as ataxia, skeletal abnormalities, destructive arthropathy. Diagnosis can be confirmed by expert metabolic centre via measurement of biomarker, its oligosaccharides in serum or urine, enzyme activity determination in serum or leukocyte, and or molecular analysis.
Another approach is looking for the rarest patient among the rare ones. Indeed, in a retrospective study for identification of alpha- menosidosis in a patient with suspicion of mycopolysaccharidosis but without diagnosis, COSMA et al. evaluate 3000 samples and they found 1.5% of patients with alpha-mannosidosis. So MPS phenotype patients that result negative for mycopolysaccharidosis should be further tested for a broader set of lysosomal disorders including alpha-mannosidosis. To conclude, I will give you some home message, alpha-mannosidosis present with a broad heterogeneity of symptoms including infection, mental retardation, motor disturbance or ataxia, skeletal abnormalities among others, with phenotypes that are not clearly distinguishable. The vast majority of patients present with conductive and neurosensorial hearing loss.
[00:24:10] Dr. Nathalie Guffon: An algorithm of diagnosis is available for alpha-mannosidosis that can guide raising the suspicion of a metabolic disorder to increase patient referral to expert metabolic centers. If an MPS-like patient test negative keep looking for a correct diagnosis and include alpha-mannosidosis in your investigation. So now we have time for the Q& A session. The first question is hearing loss and mental retardation from your study seems to be present in all cases. Is this always so? Casing to like for? Yes. Hearing loss and mental retardation are present in nearly all patients. Maybe there is only very few patients without hearing loss. and mortality detection is present. The problem is that at the beginning, they are very often classified by neuropediatrician as a borderline neurological development and maybe with the possibility to improvement. Because the first things are very few, they are able to work more or less in the normal age, even it is later, in the later stage of the normal age, but the work is not normal. They are clumsy, they fall very often. And the parent very often go to the doctor because of this, but very often it is minimized and the doctor say it will be improved when the child will be older. It is the same for the speech delay. The speech delay is often not diagnosed or recognized as very important at the beginning. And sometimes the hearing deafness is difficult to diagnose because there is also many, many OTTs with recurrent need of T- tubes. So sometimes it takes some years between the beginning of speaking of hearing impairment and the diagnosis of a neurosensorial hearing loss. So at the beginning, finally, it's mild neurologic symptom, but the association of abnormal gait, clumsy patient, hearing loss, and recurrent infection is sufficient to sink to the diagnosis because early diagnosis is very, very important to improve the outcome of this patient.
The second question is for patient one. Is two years old early for diagnosis of alpha-MAN disease to most cases? How was this caused so early, what signs? There are no more signs. It is only speech delay, hearing loss and the parent reporting difficulties. I think there is two reasons for the diagnosis and it was the parent because they were very anxious and they were sure that they were not as the two older children and the second is that they come to a good hospital and with the first investigation with a physician they were known about mucopolysaccharidosis and oligosaccharidosis. And so in the beginning, as they check for mucopolysaccharidosis because of speech delay, hearing loss, and coarse facial features and so it's not a good thing, even if they have a lot of infection. So in the beginning the doctors say it is mucopolysaccharidosis and finally to perform oligosaccharides if we ask to the lab. But it's by chance for this patient. So question is for patient two, umbilical hernia and nasal congestion but no test at that stage. Should they have tested at this stage? Yes, probably we recommend to test patient with umbilical hernia, without prematurity and recurrent ENT infection for lysosomal storage disease, not only alpha-mannosidosis, but also mucopolysaccharidosis, for example. So this child may be diagnosed at this time. It is an opposite situation. It was a poor social condition. And the patient, the parents don't think the children was ill until the school.
So the starting of the evaluation of the children was due to the teacher. More or less the same, for the second case But in real life, it's not always possible. But there is enough signs to check Case 2 and 4 age of the disease. In alpha-mannosidosis, urinary glycosaminoglycans are always normal. It's not a mucopolysaccharidosis, it's an oligosaccharidosis. So urinary GAGs are always normal, whatever the age of the patient. In this patient, the first exam performed by the physician was glycosaminoglycans because they sink to a mycopolysaccharidosis. And while this sample was normal, with a clinical manifestation, it was asked to the lab to perform also oligosaccharides. In some labs, if they have some clinical data for a patient, they perform oligosaccharides. glycosaminoglycan and the result is normal. But it's not in all labs. So it's important to check for oligosaccharides in case of normal urinary glycosaminoglycan. Because if you perform urinary glycosaminoglycan, it is because you think about a mucopolysaccharidosis or another lysosomal disease with the same presentation. Patient 4, 9 LC siblings and yet alpha-mannosidosis. is the sibling having alpha-mannosidosis normal? It's a recessive autosomal disease. So statistically, for the parent, it's one risk in 4 pregnancies. But it's like it's a chance or mention. Some people are 3 children affected and others none. And in this case, it appears that 9 children. But it's possible. As alpha-mannosidosis generally develops slower than MPS to start treatment? I don't speak about treatment, but no, it is not always too late to start treatment. The outcome is better when we start earlier. But it depends on the clinical status of the patient.
But we have some adult patients who start with enzyme replacement therapy at an adult age and show improvement, especially in infection, fatigue, pain, pulmonary function, and global general health. So it's possible. The problem is if the patient is severely affected and, for example, bedridden or in very bad clinical condition, maybe it's preferable not to start. OK, so there is no more questions. So I thank you for the attention and I will end this session. Have a nice day.